Acquired Immune Deficiency Syndrome Aids

Anthony J Pinching, Department of Immunology, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, University of London, London, UK

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

In the early 1980s, reports appeared of a new immunodeficiency disease, which was later called the acquired immune deficiency syndrome or AIDS. Over the following decade and a half, the scale of AIDS has risen from a mere handful of cases in the USA to hundreds of thousands of cases affecting most countries worldwide. The human imunodefici-ency viruses (HIV-1 and HIV-2), the causative retroviruses of AIDS, have already spread to 15-20 million individuals in less than three decades, and continue to spread rapidly in many communities, especially in the developing world. This epidemic of profound immunodeficiency, predominantly affecting cell-mediated immunity, has had a devastating and pervasive impact on many individuals and societies and has presented many challenges to immunology and to other clinical and scientific disciplines. Although an inadequate counterweight to its tragic personal and social impact, AIDS has served to focus and increase our knowledge of the immune system in health and disease as well as our understanding of individuals and of human society.


Although the first cases of AIDS were seen in homosexual men in the USA, it soon became apparent that the epidemic of HIV and AIDS was occurring more widely in North America, Europe and Australasia, not only among homosexual men but also among intravenous drug users, recipients of blood and blood products, notably hemophiliacs, and to a lesser extent among heterosexual men and women, and among children of HIV-infected women. It also gradually emerged that a substantial epidemic was affecting several regions in the developing world, such as sub-Saharan Africa and the Caribbean, with a somewhat different pattern of infection, predominantly affecting heterosexual men and women and their children, as well as recipients of blood transfusions. South America showed a mixture of the two patterns, while other regions such as the Middle East and Asia initially showed a lower incidence of a type more similar to that seen in Africa. In the late 1980s, there was a rapid expansion of the epidemics in India and South-East Asia, predominantly through heterosexual spread and among injecting drug users.

These epidemics are almost entirely due to HIV-1, although there is regional variation in serotypes. Type B virus is found mainly in the USA and Europe, while other serotypes are seen in Africa and Asia; it has recently been suggested that type E, found in parts of Thailand, may have a greater capacity for heterosexual transmission. HIV-2, a related virus, has been seen in West Africa and remains largely restricted to that region. It appears to be less readily transmissible (though by the same routes) and is also less pathogenic, but causes the same spectrum of disease as HIV-1.

Such overall patterns of spread, together with detailed case and cluster studies, indicated that HIV was spread by three routes: sexual transmission, transmission by blood and from an infected mother to the fetus. Sexual transmission could occur through penetrative intercourse between homosexual men or between men and women. Regional differences in the type of sexual spread mainly reflect differences in prevalent sexual behavioural patterns and frequency of sexual partner change. Intercurrent sexually transmitted infections, especially those associated with genital ulceration, in either partner increase the risk of transmission but are clearly not essential. Blood-borne transmission occurred through transfusion of blood or blood products, but also, on a larger scale, between intravenous drug users who shared needles and syringes and other equipment; there is a small but definite risk of infection through inoculation injury. Vertical transmission occurs in part transplacental^, in part during delivery and in part through breastfeeding, although the proportions remain uncertain. Casual transmission has not been documented.

There has been considerable interest in the possibility that individuals exposed to HIV may develop protective immunity that prevents or clears initial infection or have features that prevent or reduce the risk of subsequent infection. For example, cohorts of female prostitutes in Africa and of homosexual men include individuals who appear to have been multiply exposed but remain uninfected. These show some HLA association and evidence of HIV-specific cytotoxic immune responses. The mechanism remains obscure. Recent observations on second receptors for

HIV, which are variably expressed among some populations, raise the possibility that lack of such receptors could be protective. Some infants appear to show evidence of transient infection as evidenced by polymerase chain reaction (PCR) or viral culture in the weeks after delivery but do not seroconvert or show any other signs of infection later. It has been proposed that they have cleared the infection, although the possibility of prolonged circulation of latently infected maternal cells has not been excluded.

Spectrum of HIV infection

A person infected by HIV will, within 3 weeks to 3 months, develop a detectable antibody response and will remain HIV antibody positive thereafter. Given that HIV establishes persistent infection, antibody positivity can be taken as evidence of current infection and has been widely used clinically and epidemi-ologically as a marker.

At the time of seroconversion, a significant minority of patients develop an acute transient glandular fever-like illness, with fever, malaise, rash, sore throat, lymphadenopathy, arthralgia and headaches (HIV seroconversion illness). In a few cases there is frank encephalopathy or aseptic meningitis. It is also now recognized that some patients develop acute, transient cellular immunodeficiency, manifested, for example, by oral and esophageal candidiasis. The symptoms and signs of acute HIV infection typically resolve after a few weeks. Patients with a severe and prolonged acute illness appear to progress to AIDS more rapidly, and those who develop any symptomatic seroconversion are more likely to progress than those who do not. After the resolution of the acute illness, patients will pass into a phase of chronic symptomless HIV infection.

Chronic symptomless HIV infection may take one of two forms - patients without any abnormal physical signs and those with persistent generalized lymphadenopathy. The lymph nodes are in most instances moderately enlarged in cervical, axillary and inguinal regions (although inguinal nodes may be enlarged to a similar degree in people without HIV infection) and some other peripheral sites, such as the epitrochlear nodes. They are sometimes slightly tender and may fluctuate in size with intercurrent illness, but are otherwise unremarkable. Patients may remain symptomless, with or without enlarged lymph nodes, for many years but over time a substantial proportion go on to develop disease. The risk for developing symptomatic disease is similar for patients with and without lymphadenopathy.

A few patients with otherwise symptomless chronic infection and without immunodeficiency develop thrombocytopenic purpura. The pathogenesis of this is somewhat unclear, with evidence for platelet-specific antibodies and for immune complexes in different studies. The disorder is rarely associated with severe bleeding and seems to remit spontaneously after a few years in most cases. It does not presage progression.

With increasing years of infection, an increasing proportion of patients with chronic HIV infection will progress to develop evidence of immunodeficiency and other disease. This may initially be seen as constitutional illness (malaise, weight loss, diarrhea) or evidence of moderately severe immunodeficiency (oral candidiasis, oral hairy leukoplakia, multidermatomal shingles, salmonellosis). Patients may first develop such symptoms and later progress to AIDS, while others develop AIDS without any intervening symptomatic stage.

AIDS itself comprises two main categories: patients with major opportunist infections of cell-mediated type (e.g. Pneumocystis carinii pneumonia, cryptococcal meningitis, disseminated mycobacterial infection, cytomegalovirus retinitis), and those with opportunist tumors, Kaposi's sarcoma and B cell lymphoma. These will be considered in more detail below. It is worth noting that patients with Kaposi's sarcoma alone and some patients with lymphoma have less severe immunodeficiency than those with major opportunist infections.

In addition to the problems with cell-mediated opportunists, some patients, especially children, show significantly increased susceptibility to infections with capsulated bacteria of a type more typically associated with humoral immunodeficiency. This results from the dysglobulinemia seen in HIV infection, in which there is immunoglobulin G2 (IgG2) subclass deficiency and impairment of specific antibody development against antigens not previously encountered. These infections can occur with increased incidence in people with otherwise symptomless infection.

As well as its immunopathogenic effects, HIV can also cause chronic progressive disease of the nervous system, including HIV encephalopathy (or AIDS dementia complex), vacuolar myelopathy, peripheral and autonomic neuropathy, and occasionally an inflammatory myopathy. The central nervous system disorders typically occur after the onset of immunodeficiency disease, but go on to affect a high proportion to varying degrees.

A variety of other clinical disorders are seen, including: lymphocytic interstitial pneumonitis and an associated chronic lymphocytic parotitis, which are commonly seen in children but rarely in adults:

the appearance or increased severity of psoriasis and Reiter's syndrome and other seronegative arthropathies; HIV enteropathy with partial villous atrophy; and recrudescence of atopic disease in predisposed subjects.

Clinical features of AIDS

The profound and progressive immunodeficiency seen in AIDS is broadly characterized by infections with facultative intracellular and related pathogens and herpesviruses, and by opportunist tumors. While some of these pathogens only cause disease in immunodeficient subjects, others show altered and enhanced pathogenicity, causing different clinical disorders or more disseminated disease. The profile of these infections shows regional variation determined by locally prevalent pathogens and risk behaviour, which also affect the likelihood of infection by the relevant organisms, many of which are latent in the immunocompetent host.

Common and early infections in AIDS include Pneumocystis carinii pneumonia, disseminated tuberculosis, esophageal candidiasis, cryptococcal meningitis and ulcerative mucocutaneous herpes simplex infection. Other common infections seen, typically later in the course of the progressive decline in cell-mediated immunity, include cerebral toxoplasmosis, cytomegalovirus disease (presenting as retinitis, colitis, esophagitis and adrenalitis and, less often, pneumonitis, encephalitis and radiculitis), disseminated Mycobacterium avium intracellular infection, histoplasmosis, gastrointestinal cryptospori-diosis, progressive multifocal leukoencephalopathy, visceral leishmaniasis, disseminated penicilliosis, nocardiosis and disseminated strongyloidiasis. Some of these organisms present predominantly in one organ system - lungs, gut, central nervous system, lymph nodes - but may also show varying degrees of dissemination.

Kaposi's sarcoma, which is most common among homosexual men and among heterosexually acquired cases of HIV in the developing world, is thought to result from infection with a newly recognized human herpesvirus, HHV-8. It often presents as cutaneous disease, later progressing in some patients to affect lymph nodes, lungs and gastrointestinal tract. Severe visceral disease more commonly presents early in patients in Africa. B cell lymphoma, of a variety of histological types, may present as isolated cerebral lymphoma or as systemic disease, with frequent extranodal involvement. Hodgkin's lymphoma, seminoma, squamous carcinoma of the anorectal region, cervical carcinoma and acute myeloid leukemia have also been observed somewhat more frequently in HIV-infected subjects, although the association is less clear.

Natural history of HIV infection

The risk of development of disease in HIV-infected subjects has been assessed in large cohort studies. These have shown that in rime the majority will develop AIDS (50% in 10 years; 65% in 14), with others progressing to less severe symptomatic HIV disease. It is now recognized that a small proportion of patients remain well and without evidence of immunodeficiency for 10 or more years. It is not clear whether they represent a discrete group or simply those with much slower progression rates. They are the subject of many studies attempting to define whether there are immune or other protective mechanisms.

Several factors affecting the likelihood of progression in HIV-infected subjects have been identified. Increased risk of disease and of immunological decline has been shown in patients with the HLA-Al, -B8, -DR3 haplotype in cohorts of hemophiliacs and homosexual men and HLA-B35 may also increase the risk of progression. In some ethnic groups HLA-DR5 is associated with increased risk of Kaposi's sarcoma. Patients with HLA-B27 appear to have a lower risk of progression.

Intercurrent infections may also affect progression: evidence of such an effect has been shown for sexually transmitted infections among homosexual men and for cytomegalovirus infection among hemophiliacs. It is plausible that other infections may have a similar effect, including systemic bacterial infections in injecting drug users using unsterile equipment, and possibly some of the infections that result from immunodeficiency, such as tuberculosis, listeriosis and pneumocystosis.

Age may also have some effect. This is most clearly seen in children infected in the neonatal period who show a much higher proportion of rapid progressions than adults. This is unlikely to reflect immunological immaturity and may result from immunological activation during the acquisition of an immunological repertoire. Children over 4 years of age show similar progression rates to adults. Adults over 50 years of age may also have slightly increased risk of progression.

The effect of pregnancy is controversial. Early studies that were carried out on women who had already given birth to a child with AIDS showed that subsequent pregnancies were associated with increased risk of progressive disease in the mother. More recent studies on women having their first HIV-positive pregnancy indicate no increased risk. It is possible to reconcile these findings by concluding that having more than one HIV-positive pregnancy increases the risk to the mother.

Although formal epidemiological data are lacking, it is plausible that malnutrition, which itself induces cell-mediated immunodeficiency, may enhance the risk of progression to HIV disease. A higher rate of progression has been reported in a prospectively studied cohort in Uganda; several factors could have contributed to this, including different viral strains, different human genotypes, intercurrent parasitic and other infections and nutritional state. The use of immunosuppressive drugs such as prolonged high doses of corticosteroids may enhance risk.

The overall picture is one where increased risk of progression is associated with events that may activate the immune system, and thus active CD4 lymphocytes and macrophages which are latently infected with HIV, hence increasing virus replication, cell-to-cell spread and progressive immunological decline, as well as with events that suppress cell-mediated immune responses, thus compounding the factors leading to immunological deterioration.

Some strains of virus, whether the initially infecting virus or one that emerges through mutation within the infected host, may have greater pathogenic potential. One transfusion-associated cluster of HIV infections has been reported in which long-term nonprogression was a feature and where the HIV strain had a defective nef gene; this does not appear to be a generalizable feature but indicates the role of viral genotype, as do the lower rates of progression with HIV-2.

The role of protective immunity, whether humoral or cell mediated, is far from clear. Neither neutralizing antibody titer nor HIV-specific cytotoxicity, whether of antibody-dependent type or major histocompatibility complex (MHC)-restricted type, have any consistent relationship with progression. These responses are present throughout the spectrum of HIV infection and disease. It remains to be established whether or not innate resistance or susceptibility to HIV infection or disease play any part, or whether genetic factors serve rather to influence the ease with which, for example, immunological activation by intercurrent events is achieved, as is implied by the association with the HLA-A1, -B8, -DR3 phenotype. The study of long-term nonpro-gressors has attempted to elicit evidence of special features associated with nonprogression but has not yet shown any unique or general characteristic of host or virus. One problem with such studies is that of finding an appropriate comparator group, as their rapidly progressing peers may already have died and current rapid progressors may have different initial host and viral characteristics.

Predictive markers for progression

Another objective of cohort analysis has been the identification of markers that can predict risk of future progression in HIV-infected subjects. The numbers of CD4 cells in blood have been widely used in this way, not least because they can reflect a significant component of the pathogenesis of disease. In grouped data over long-term follow-up, falling CD4 counts are strongly associated with progression. However, there is considerable variability in individual trends and, as many other factors can affect CD4 count, CD4 counts must be used with caution in individual patients. Serum markers of immunological activation such as [^-microglobulin, neopterin and interleukin 2 (IL-2) receptor are also associated with an increased risk of progression, as are raised IgA levels. The CD8 count may rise during the early years of HIV infection and then fall in the 2 years before progression, but the predictive value is unclear. CD8 derived cytokines may inhibit virus spread.

Virological markers are also of value. In early studies, HIV p24 antigenemia was strongly associated with progression in patients in temperate climates, although a significant proportion of AIDS patients do not develop antigenemia. Prior to the appearance of HIV p24 antigen, antibody levels against p24 fall, perhaps reflecting the complexing of p24 antigen and antibody following increased virus replication. Reduced levels of antibodies to pi 7 and to reverse transcriptase may show similar trends. These changes are not seen in patients in tropical environments, perhaps due to increased polyclonal B cell activation due to parasitic and other infections. It is evident that p24 antigen is an imperfect and crude index of virus replication.

Recently, it has become possible to measure viral load by quantitative PCR. Studies on a large prospective cohort of HIV-infected individuals have shown that viral load measures on initial samples provide a powerful predictive marker for subsequent progression. Such tests appear to be more discriminatory than CD4 count alone. Such findings are likely to provide a valuable means of assessing prognosis and suitability for antiretroviral therapy. They may help to identify those subjects with a high CD4 count who do poorly and those with a low CD4 counts who do well. Although the use of the two markers in conjunction has yet to be analyzed, this is likely to be a particularly useful combination for assessing future progression. Longitudinal analysis of both markers may add further value. Earlier data showed that combining CD4 counts with serum neopterin, IgA, IL-2 receptor and p24 antigen could provide a better prediction of outcome than CD4 alone, although these are likely to be superseded by viral load measures, which probably correlate with activation markers.


HIV is a retrovirus, having an RNA gene that encodes for reverse transcriptase, which allows a DNA copy of the virus to be made. This DNA copy is then spliced into the gene of the infected cell, through the action of virally encoded endonuclease, leading to persistent and typically productive infection.

A major HIV gene product is the outer envelope glycoprotein gpl20, which is expressed on the surface of the virus and of infected cells, and contains a region which binds with high affinity to the CD4 molecule on host cells. CD4 thus acts as the main virus receptor, enabling HIV gpl20 to target cells of the immune system for infection and subsequent damage. Second receptors (CXCR4 and CCR5) for HIV on CD4 T lymphocytes and on antigen-presenting cells are a family of transmembrane proteins which are physiological receptors for chemo-kines. They appear to be critical to fusion events and cellular infectivity, and may also explain data showing that combinations of chemokines (RANTES, MlP-la and MIP-10) can inhibit cell-to-cell infection in vitro.

After the attachment of gpl20 to CD4 and the second receptor on lymphocytes or macrophages, the virus membrane fuses with the membrane of the CD4-bearing cell, internalizing the virus genome and leading to cellular infection. This occurs both in initial infection and in the gradual process of cell-to-cell spread within the body that leads ultimately to disease. Infection of CD4 lymphocytes is central to the immunopathogenetic effects of HIV. Macrophages and related cells can also be infected by routes other than CD4 binding, e.g. Fc or C3b receptor binding. Such cells serve as an important reservoir of HIV infection and are implicated in the neuropathogenesis of HIV encephalopathy. Recent data have emphasized that most cell-to-cell infection occurs in lymphoid tissue, where extensive viral replication has been documented. As disease progresses, this results in significant structural damage to these key microenvironments.

The viral replication cycle proceeds at a rapid rate in infected patients, with durations of as little as 2.6 days, giving some 140 generations each year. This, combined with the error-prone transcription of retroviral genes, gives the opportunity for enormous diversity of viruses within any individual. It is against this background that pathogenetically diverse strains, such as syncytium-inducing strains, and drug-resistant strains may emerge. In turn these affect the rate of immunological decline and responsiveness to therapy.

The most striking and most consistent effects of HIV in progressive disease are a reduction both in the number and in the function of CD4 lymphocytes. Infection of CD4 lymphocytes by HIV leads to their premature death or rapid elimination, so that few viable circulating CD4 cells show evidence of infection at any time, yet their numbers are progressively depleted. This may be due to virus cytopathic effects or to host-mediated cytotoxicity, or both. Virus-induced damage includes cell lysis and, more importantly, apoptosis and the formation of syncytia by fusion of infected as well as uninfected CD4 lymphocytes.

In addition to the progressive attrition of CD4 lymphocytes, various defects in the function of the CD4 cells that remain have been shown, even though most of them are uninfected at the time. These include failure of T cell responses to antigen, to T cell mitogens (phytohemagglutinin, concanavalin A) and to T cell-dependent B cell mitogen (poke-weed), whether measured by proliferation or cytokine/antibody production. Impaired cytokine release is seen for IL-2 and macrophage-activating cytokines such as interferon -y, as well as cytokines involved in regulating B cell responses. It seems that the failure of these mechanisms is largely responsible for the defects in killing of facultative intracellular pathogens, failure to control virally-induced tumors and herpesvirus infection and for some of the B cell defects seen in patients.

One common means whereby these effects on CD4 cell function could be mediated by HIV has been shown. HIV infection of lymphocytes in vitro or exposure of uninfected lymphocytes to gp!20 causes activation of the inositol polyphosphate (InsP) signal transduction pathway; this causes a rise in resting levels of InsP3 and InsP4, and hence of intracellular calcium. This leads to a state of chronic cellular activation, rendering the cells less responsive to new signals. Similar changes are seen in lymphocytes taken from patients. These effects may be mediated by binding to CD4 and subsequent alterations in the intracellular signaling pathways involving tyrosine phosphorylation, starting with p 56lck. Similar changes in activation are seen in macrophages and it is possible that similar effects underlie the effect of HIV proteins on B cell function.

Depletion of CD4 lymphocytes and their functional impairment has knock-on effects on many other cells, in addition to any direct effects that HIV has on them. Patients' macrophages show impaired microbicidal activity for intracellular pathogens in the presence of cytokines produced by autologous lymphocytes, although they retain responsiveness to exogenous interferon 7. Other macrophage functions, including antigen-presenting function and receptor expression, show changes that may result from loss of CD4 lymphocyte signals or from HIV infection. Dendritic cells, which may be infected by HIV, may be depleted and show marked dysfunction in antigen-presenting activity from an early stage of HIV infection. Natural killer (NK) cells and other cytotoxic cells show reduced recruitment and activity, in part due to reduced IL-2 and interferon 7 production.

CD8 T lymphocytes are clearly altered in number with disease progression (see above) and show increased activation markers. Previously thought not to be infected, a recent report suggests that they may indeed be infected especially in patients with advanced disease, possibly as a result of infection of thymic precursors which coexpress CD4. This may contribute to the decline in their number in late disease and to their functional abnormalities. Furthermore, CD8 cells produce factors, which may include chemokines acting on the second receptor and/or other factors, that inhibit viral infection of CD4 cells. If these in vitro effects are operative in vivo, they may act to control or contain viral replication earlier in HIV infection. This is in addition to any role of CD8 cell-mediated specific cellular cytotoxicity, discussed above.

B cells show polyclonal activation in HIV-infected subjects, notably those with persistent generalized lymphadenopathy and Kaposi's sarcoma, with raised IgGl, IgG3, IgA, IgE and IgM levels. IgG2 and IgG4 levels may be low. Spontaneous immunoglobulin production is increased and responses to T cell-independent antigens are reduced. Enhanced B cell IgD production and raised serum IgD levels imply increased immaturity of B cells, which is also suggested by phenotypic alterations. In addition, responses to B cell mitogens and T cell-dependent mitogens and antigens are impaired, whether at a T cell level, antigen-presenting cell level, B cell level or a combination of any of these. Follicular dendritic cells in lymph nodes, which show evidence of HIV infection, show progressive destruction in patients with symptomatic HIV infection and AIDS. As a result of these various defects, patients show increased levels of antibodies to previously encountered antigens but are unable to develop new antibody responses.

The neuropathogenesis of HIV encephalopathy and other nervous system disorders is more obscure. However, HIV encephalopathy also appears to result from both loss of cells and defective function of those that remain. The main cell type in the nervous system that harbours HIV is the macrophage, including perivascular macrophages and microglia, with little indication of infection of neuronal or glial elements. It is likely that HIV infection of such cells causes release of virus proteins or macrophage products, which in turn damage or alter the function of neighbouring nerve cells. gpl20 can interfere with neuronal function in a similar way to that seen in lymphocytes, with activation of signal transduction pathways and raised intracellular calcium.

Treatment strategies in HIV disease

The AIDS pandemic has meant that large numbers of patients with severe immunodeficiency now require health care provision. Such patients need substantial specialist input from a wide variety of medical disciplines as well as a wider multidisciplinary team. Accessible and appropriate health care systems are being developed to cater for the various stages of HIV disease. Patients are increasingly involved in aspects of their care, notably in health maintenance (avoiding undernutrition, smoking, alcohol excess, and other cofactors). Specific therapies are of three types: treatment/prophylaxis of opportunist diseases, antiretroviral therapies and immunorestorative approaches.

Many of the opportunist infections are readily manageable, especially in the earlier stages of AIDS, with the use of specific antimicrobials and antitumor therapies. For many of the infections, maintenance therapy is required to avoid relapse. For some common infections, the use of antimicrobial prophylaxis offers considerable benefit, although there is often a trade-off of toxicity or drug hypersensitivity. Indeed drug hypersensitivity (type 1 and/or type III) to sulfonamides, antifungals and other drugs is notably more common in these immunodeficient patients. The increasingly effective use of antimicrobial treatment and prophylaxis has changed the clinical profile of disease, with deferral or elimination of some opportunistic events and decreased morbidity. However, it presents further challenges as more patients have more prolonged periods of severe immunodeficiency, leading to a greater proportion being affected by the less treatable infections and tumors, and new and more complex clinical events.

Antiretroviral therapy has developed rapidly in recent years. Zidovudine (AZT), a reverse transcriptase inhibitor and the first agent to show clinical efficacy, has had a significant impact when given as monotherapy in AIDS and symptomatic HIV infection, reducing viral replication and hence reducing the rate at which disease progresses. This led to valuable increases in length and quality of life; improvement in HIV encephalopathy and reduction in its incidence are other notable benefits. Myelosuppres-sion, gastrointestinal symptoms and a mitochondrial myopathy are seen, particularly at high doses, in patients with more advanced disease or where other drugs add to these problems. The benefit of zidovudine monotherapy seems on average to wane after some 2 years, whether due to its intrinsic limitations or the emergence of viral resistance. A logical approach to antiviral therapy would be to start treatment earlier, while the virus is active but when immune destruction is not so far advanced. With zidovudine alone, despite early encouragement, there is no general benefit in terms of clinical outcome. Zidovudine has, however, been shown to decrease vertical transmission if given to mothers during pregnancy and to the neonate.

Given the nature of the viral challenge, the use of combination therapies seems highly appropriate, with the objective of increasing efficacy and inhibiting the emergence of viral resistance, and possibly reducing toxicity. Initially this approach was focused on other nucleoside analogues, such as didanosine, zalcitabine, lamivudine and stavudine. Recent studies have shown the greater and more prolonged clinical efficacy of dual therapy with pairs of nucleoside analogs, confirming earlier studies showing their greater impact on CD4 count and on viral load. These therapies appear to offer some efficacy in earlier stages of infection, but the optimal timing is uncertain.

Two other major classes of antiretroviral agents have emerged - non-nucleoside reverse transcriptase inhibitors (NNRTI) (e.g. nevirapine, delavirdine, loviride) and protease inhibitors (e.g. saquinavir, ritonavir and indinavir). Triple combinations (e.g. two nucleosides and an NNRTI, or two nucleosides and a protease inhibitor) have an even more potent and durable impact on markers and, at least on early evidence, on clinical outcomes than two-drug regimens. Viral resistance appears to be more profoundly inhibited, which offers encouraging prospects for long-term efficacy. These more substantial effects raise the possibility of much earlier treatment, and some studies are exploring the effect of treating at or around the time of seroconversion.

Many issues still need to be resolved regarding antiretroviral therapy: optimal timing; optimal initial combinations; suitable means of monitoring patients on treatment; how these can inform decisions about if and when to change and, if so, what to change to;

and appropriate sequences of therapy. While some further approaches to antiviral treatment are being studied, the current portfolio of three classes seems likely to remain the core of treatment for some time, and there is a need to ensure that the armamentarium is deployed most effectively.

Among antiretroviral approaches that have been tried was the use of soluble CD4 or CD4 linked to an Fc molecule as a decoy for viral gpl20. This looked promising in vitro and appeared not to interfere with cell function, but in vivo results were disappointing. This may be for a number of reasons, including the need to achieve very high levels to inhibit viral spread, the short plasma half-life of CD4 and the probability that much cell-to-cell transmission occurs directly, without a fluid phase.

Immunological approaches to therapy have been disappointing to date, although most were tried before effective antiretrovirals were available. Some are being re-explored in combination with antiretroviral therapy. Bone marrow transplantation has been generally disappointing, even when combined with antivirals. Several cytokines have been tried, including IL-2 and interferon -y, with some encouraging in vitro changes, and these are being tried with antiretrovirals. Immunostimulation has always been hard to achieve in reality and no clear agent of this type has been shown to be effective. One trial has shown that inosine pranobex (isoprinosine) may delay disease progression when given to asymptomatic patients, but other trials have not confirmed this; the mechanism of action is not clear.

Immunoglobulin therapy has proved helpful in patients, especially children, with antibody deficiency, by reducing problems with pyogenic infections. HIV antibody from asymptomatic subjects has been used as passive specific antibody therapy in a few studies but the results are not impressive and do not suggest that any effect is necessarily due to an antiretroviral mechanism; it is doubtful that passively acquired antibody will be any better than that produced actively in stemming viral replication and cell-to-cell transmission. Some have suggested that immunization with certain HIV antigens may be effective but such approaches may be subject to similar provisos; recent reports of therapeutic vaccines show no benefit with envelope glycoprotein or p24.


Extensive work is being done to develop vaccines against primary HIV infection. This work has utilised gpl20 or other viral proteins and has employed a variety of viral and other vectors. Antibody and cytotoxic responses can be readily obtained, but most work in animals shows that infection is not prevented or is restricted to a few strains. It remains unclear whether these problems reflect limitations of the immune responses obtained with such approaches or whether they reflect the fact that in most cases primary infection of target cells occurs at the mucosal level, where contact between virus and macrophage or lymphocyte is unlikely to be impeded by such antibody as reaches that site. Some studies have examined ways of producing more substantial mucosal immunity and this would seem a critical element in any vaccine approach. The prospect of an effective vaccine in the imminent future seems remote.

See also: Chemokines; Chimerism, hematopoietic; Dendritic cells; Human immunodeficiency viruses; Opportunistic infections; Retrovirus, infection and immunity.

Further reading

Barre-Simoussi F (1996) HIV as the cause of AIDS. Lancet 348: 31-35.

Bloom BR (1996) A perspective on AIDS vaccines. Science

111-. 1888-1890. Carpenter CCJ, Fischl MA, Hammer SM et al for the International AIDS Society - USA (1997) Antiretroviral therapy for HIV infection in 1997. journal of the American Medical Association 277: 1962-1969. Corey L and Holmes KK (1996) Therapy for human immunodeficiency virus infection - what have we learned? New England Journal of Medicine 335: 1142-1144.

de Boer RJ and Boerlijst MC (1994) Diversity and virulence thresholds in AIDS. Proceedings of the National Academy of Sciences of the USA 91: 544-548.

de Vita VT Jr, Hellman S and Rosenberg SA (eds) (1997) AIDS: Etiology, Diagnosis, Treatment and Prevention, 4th edn. Philadelphia: Lippincott-Raven.

Feinberg MB and McLean AR (1997) AIDS: decline and fall of immune surveillance. Current Biology 7: R136-140.

Fowke KR, Nagelkerke NJD, Kimani J, Simonsen JN et al. (1996) Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya. Lancet 348: 1347-1351.

Haynes BF, Pantaleo G and Fauci AS (1996) Toward an understanding of the correlates of protective immunity to HIV infection. Science 271: 324-328.

Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373: 123-126.

Kaslow RA, Carrington M, Apple R, Park L, Munoz A, Saah AJ et al (1996) Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection Nature Medicine 4: 405-411.

Levy JA (1996) Infection by Human Immunodeficiency Virus - CD4 is not enough. New England Journal of Medicine 335: 1528-1530.

Mellors JW, Rinaldo CR, Gupta P, White RM, Todd JA, Kingsley LA (1996) Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272: 1167-1170.

Saag MS, Holodniy M, Kuritzkes DR at al (1996) HIV viral load markers in clinical practice Nature Medicine 2: 625-629.

Ng TTC, Pinching AJ, Guntermann C and Morrow WJW (1996) Molecular immunopathogenesis of HIV infection. Genitourinary Medicine 72: 408-418.

Quinn TC (1996) Global burden of the HIV pandemic. Lancet 348: 99-106.

Rosenberg PS (1995) Scope of the AIDS epidemic in the United States. Science 270: 1372-1375.

Weiss RA (1996) HIV receptors and the pathogenesis of AIDS. Science 111-. 1885-1886.

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