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HIV Pathogenesis

The pathogenesis of HIV disease, from a virological and immunological standpoint, has been studied intensively and defined progressively over the past 20 years.[6,8] The pathogenic mechanisms of HIV disease are extremely complex and multifactorial[27] (Fig. 1). Even before HIV was identified, it was recognized that an apparent paradox existed whereby the immune system was aberrantly activated at the same time that the individual was experiencing immune deficiency.[5] This was later shown to be due to a combination of the aberrant secretion of various cytokines, many of which could upregulate virus expression, and the intensive cell signaling induced by the viral envelope.[28] Depletion of CD4+ T cells was recognized as a hallmark of disease early on,[11,12] even before the classic demonstration in 1984 that the CD4 molecule was the primary receptor for the virus on a subset of T cells and monocytes.[29,30] In addition, much evidence suggested that other factors were necessary for HIV fusion and entry, but these putative 'coreceptors' remained elusive for several years.[31]

Pathogenic events in untreated HIV-mediated disease. HIV (pink) enters the body and binds to Langerhans or dendritic cells (orange), which carry the virus to CD4+ T cells. Infected CD4+ T cells home to lymphoid tissue, where the infection is established. Virus replication accelerates, and massive viremia leads to the wide dissemination of virus throughout the body's lymphoid tissue. An HIV-specific immune response occurs and virus is trapped on the follicular dendritic cells of germinal centers in the lymphoid tissue. At this point, chronic, persistent infection is established despite an immunological response to the virus. Immune activation is an important driver of HIV replication and is mediated by the secretion of various cytokines and by aberrant cell signaling caused by interaction of the viral envelope with cellular receptors. Because there is usually only partial immunological control of virus replication, continual and accelerated production of virus ensues. This is associated with a rapid turnover of CD4+ T cells. Ultimately, lymphocyte depletion occurs, along with destruction of the architecture of lymphoid tissue. Adapted with permission from ref. 6.

In the mid-1990s, a number of diverse areas of investigation elucidated the roles of the chemokine receptors CXCR4 and CCR5 in the efficient binding and entry of two different strains of HIV-1 called X4 and R5, respectively.[6,31] Indeed, RANTES, MIP-1 and MIP-1 , the ligands for CCR5, were shown to potently inhibit the binding of virus to its target cell. This recognition that HIV could use different coreceptors also helped to explain the occurrence of syncytial (CXCR4-using) and nonsyncytial (CCR5-using) variants of HIV.[6] The importance of the CCR5 coreceptor in the pathogenesis of HIV infection was proven by the finding that cells from individuals homozygous for a deletion of 32 base pairs in the CCR5 gene could not be infected in vitro with R5 viruses and that such individuals, who comprise about 1% of white populations, are extremely resistant to HIV infection even when repetitively exposed to virus.[32]

Studies of lymphoid tissue in individuals infected with HIV revealed the disseminated nature of HIV infection and the fact that lymphoid tissue is indeed the chief target and reservoir of HIV infection.[33,34] In addition, it became clear that HIV continually replicates at varying degrees in lymphoid tissue despite the fact that the individual might appear to be clinically well. Although the clinical course varied widely among individuals, the inexorably progressive nature of disease in most individuals became clear.

An important advance in HIV research has been the development of highly sensitive techniques for the precise quantification of small amounts of nucleic acids.[35] The measurement of serum or plasma levels of HIV RNA is now an essential component of the monitoring of individuals with HIV infection and, together with CD4+ T cell counts, guides therapeutic decisions.[36] Assays such as RT-PCR and the bDNA technique for directly detecting HIV RNA have helped to clarify the direct relationship between amounts of virus and rates of disease progression, rates of viral turnover, the relationship between immune system activation and viral replication, and responsiveness to therapy.[6]

The ability to measure plasma viremia precisely led to the classic viral dynamics studies of Ho and Shaw in 1995, which characterized the enormous turnover of virus in HIV disease and the delicate balance between virus production and T cell dynamics.[37,38] These studies led to a cascade of insights into HIV pathogenesis, among them an appreciation of the direct relationship between virus replication and disease progression and the association of a given viral set point in an untreated individual with the prognosis for disease progression.[39] The latter observation has been essential in the design of therapeutic strategies and has guided clinicians in decisions regarding the initiation and modification of therapeutic regimens.[36]

The finding of latent reservoirs of HIV, particularly in the resting subset of CD4+ T cells, has had a sobering effect on hopes of eradicating HIV in individuals whose viral load is rendered 'undetectable' by antiretroviral therapy.[40] Indeed, simple but defining studies have shown that even in individuals in whom plasma viremia is driven by antiretroviral therapy to levels of less than 50 copies of RNA per ml ('undetectable') for up to 3 years, the viral reservoir persists and the virus rebounds from this reservoir within weeks of discontinuing therapy.[41]

Studies of the immune response to HIV have been both productive and frustrating. Clearly, individuals in whom HIV infection has been established cannot eliminate the virus from their bodies.[40,41] Despite this consistent observation, individuals infected with HIV also show several elements of HIV-specific immunity. Neutralizing antibodies, potent HIV-specific CD8+ cytotoxic T cell responses and HIV-specific CD4+ T cells are present in many individuals infected with HIV at various stages of disease.[6] Unfortunately, CD8+ cytotoxic T cells select for escape mutants, and the most effective neutralizing antibodies are directed at cryptic epitopes against which it is difficult to induce antibodies. Although CD4+ T cells capable of undergoing lymphocyte blast transformation to HIV antigens are more likely to be seen in individuals in the early stages of disease, the induction of such responses has minimal, if any, effect on disease progression.[6]

Thus, the initial hope that the identification of HIV-specific elements of the immune system in HIV-infected individuals would lead to better therapies and vaccines has been replaced by the realization that we have yet to identify a clear correlate of protective immunity against HIV infection.[42] Understanding the correlates of immune protection and their potential role in vaccine development remains one of the greatest challenges in HIV and AIDS research.

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