Where does HIV live?

The worldwide dissemination of Human Immunodeficiency Virus (HIV) over the past four decades is one of the most catastrophic examples of the emergence, transmission and propagation of a microbial genome. We now know that the cellular and anatomical sites of HIV replication influence the course of the infection, the ability of antiretroviral therapy to reduce viremia and the establishment of the viral reservoir. This highly mutable virus inserts its genome into the genomes of crucially important cells of the host and despite therapy, maintains a reservoir of latent HIV within the body. The virus has a predilection for activated HIV-specific CD4+T cells, although other cells are also susceptible to the virus. This tropism for particular cells is determined mainly by cellular receptors to which HIV attaches in order to enter cells. In this review, the anatomical localization will be discussed.

The anatomical home of HIV
Lymphoid organs

The tissue distribution of target cells defines the anatomical reservoirs of HIV. In acute infection, the mucosa is the dominant site of infection. The gastrointestinal tract and other mucosal tissues contain at steady state and many of them are in an activated state. During acute HIV infection, the virus rapidly multiplies and propagates in the lymphoid component of mucosal tissues, thereby profoundly affecting the immune system soon after infection. In macaques infected with SIV, intestinal CD4+T cells are almost entirely depleted within three weeks after infection.

During the acute phase and into the chronic phase of infection, the sites of HIV replication begin to include other peripheral lymphoid organs. High levels of HIV accumulate in lymph-node follicular dendritic cells, which are of epithelial origin and therefore distinct from the dendritic cells of hematopoietic origin. These cells may become a major reservoir of infectious HIV in the later stages of infection. There are many more infected cells in lymph nodes than in the blood (which in any case contains fewer than 2 per cent of total body lymphocytes). Indeed, ongoing high-level viral replication and the ensuing activation of T cells within the lymph nodes may be responsible for the destruction of lymph-node architecture that is typical of the infection.

The primary sites of lymphopoiesis -- the thymus and bone marrow -- may also be sites of HIV replication. In both children and adults, HIV infection causes involution of the thymus and depletion of thymocytes. Thymocytes at almost all stages of maturation are targets of HIV infection.

The central nervous system

The capacity of HIV to cause disease in the central nervous system suggests that the virus may persist and replicate there. Viral particles have been identified in brain-derived macrophages and microglia and isolated from the cerebrospinal fluid. In patients with neurologic symptoms associated with AIDS, HIV-specific antibodies have been detected in the cerebrospinal fluid. HIV isolated from cerebrospinal fluid tends to be more macrophage-tropic than does virus circulating in plasma, and thus HIV replication may be compartmentalized in the central nervous system. The HIV transactivating factor Tat, which is taken up into neurons by means of CD91, is thought to exert neurotoxic effects by increasing the production of nitric oxide and interfering with the integrity of the blood brain barrier.

The penetration of antiretroviral drugs into the central nervous system and the maintenance of high therapeutic levels of these drugs are matters of concern, since the levels of all classes of antiretroviral agents are lower in the cerebrospinal fluid than in the plasma. Indeed, different patterns of drug resistance mutations have been observed in viral isolates from paired samples of plasma and cerebrospinal fluid from patients who are following nonsuppressive antiretroviral regimens. Thus, the central nervous system may act as a reservoir for replication of HIV even during maximal treatment with antiretroviral agents.

The genitourinary tract

The blood-testis barrier does not prevent virus from reaching semen. HIV replication has been detected in T cells and macrophages present in semen and within the renal epithelium. In situ hybridization of renal biopsy tissue from patients with HIV nephropathy suggests the presence of a reservoir of HIV, even in patients with undetectable levels of viral RNA in plasma. Similarly, HIV has been detected in macrophages and lymphocytes within the cervix. As with the virus that is found in cerebrospinal fluid, the genotypic and phenotypic compartmentalization of HIV from genital secretions suggests that antiretroviral drugs have difficulty penetrating into this site. These factors clearly affect not only the course of the infection within individual patients, but also the transmission of the virus to sexual partners.

Future perspectives

HIV infection appears to be a zoonosis, with AIDS resulting from the failure of HIV to adapt to a relatively new host or perhaps a failure of humans to adapt to a relatively new host, or perhaps a failure of humans to adapt to HIV infection. Either mechanism suggests that HIV and humans will eventually adapt and coexist, akin to the situation observed in natural SIV infection of chimpanzees and certain old world monkeys, clearly. The epidemic has already caused dramatic shifts in mortality within human populations worldwide. Evidence is also emerging that immunologic pressure against HIV in human hosts is causing population-dependent genetic changes in the virus itself. For example, the immunogenicity of regions of the virus that are potential targets for CD8+T cells restricted through the more common HLA class I alleles has been widely eliminated from the pool of viruses circulating in the human population. This suggests that the viruses currently infecting people already reflect the changes of an evolving host-pathogen relationship.

Although the eradication of HIV is a daunting task the goal of long-term containment of viral replication and prevention of immune dysfunction is eminently achievable. It is unlikely that current or more potent drug regimens, even if initiated early, will be able to eradicate virus within an infected person, since the T-cell reservoir of virus diminishes too slowly. Attempts to interrupt therapy in a structured fashion, aimed variously at reducing the toxic effects of the drugs or boosting HIV-specific immunity, have unfortunately failed to prove feasible because the virus inevitably and rapidly reemerges. However, the reactivation of latent reservoirs in order to "flush out" and then tackle the virus is currently a subject of intense and promising investigation. Such alternative strategies are critical, since drug-related toxic effects are becoming one of the major obstacles to long-term therapy.

Source: THE LANCET, April 29, 2004 / The Daily Star (Oct 24, 2004)