A. Overview of Course of HIV Infection

The typical course of untreated HIV infection spans about a decade (Figure 1). Stages include the primary infection, dissemination of virus to lymphoid organs, clinical latency, elevated HIV expression, clinical disease, and death. The duration between primary infection and progression to clinical disease averages about 10 years. In untreated cases, death usually occurs within 2 years after the onset of clinical symptoms.

Fig1. Typical course of untreated HIV infection. During the early period after primary infection, there is widespread dissemination of virus and a sharp decrease in the number of CD4 T cells in peripheral blood. An immune response to HIV ensues, with a decrease in detectable viremia followed by a prolonged period of clinical latency. Sensitive assays for viral RNA show that virus is present in the plasma at all times. The CD4 T-cell count continues to decrease during the following years until it reaches a critical level below which there is a substantial risk of opportunistic diseases. (Reproduced with permission from Fauci AS, Lane HC: Human immunodeficiency virus disease: AIDS and related disorders. In Longo DL, Fauci AS, Kasper DL, et al (editors). Harrison’s Principles of Internal Medicine, 18th ed. McGraw-Hill, 2012. © McGraw-Hill Education.)

Following primary infection, there is a 4- to 11-day period between mucosal infection and initial viremia; the viremia is detectable for about 8–12 weeks. Virus is widely disseminated throughout the body during this time, and the lymphoid organs become seeded. An acute mononucleosis like syndrome develops in many patients (50–75%) 3–6 weeks after primary infection. There is a significant drop in numbers of circulating CD4 T cells at this early time. An immune response to HIV occurs 1 week to 3 months after infection, plasma viremia drops, and levels of CD4 cells rebound. How ever, the immune response is unable to clear the infection completely, and HIV-infected cells persist in the lymph nodes.

This period of clinical latency may last for 10 years or more. During this time, there is a high level of ongoing viral replication. It is estimated that 10 billion HIV particles are produced and destroyed each day. The half-life of the virus in plasma is about 6 hours, and the virus life cycle (from the time of infection of a cell to the production of new progeny that infect the next cell) averages 2.6 days. CD4 T lymphocytes, major targets responsible for virus production, appear to have similar high turnover rates. Once productively infected, the half-life of a CD4 lymphocyte is about 1.6 days.

Viral diversity studies have shown that in most cases of sexual transmission a single HIV variant establishes a new infection. Early in infection, viral sequences are quite homogeneous, but because of rapid viral proliferation and the inherent error rate of the HIV reverse transcriptase, quasispecies of virus accumulate. It is estimated that every nucleotide of the HIV genome probably mutates on a daily basis.

Eventually, the patient develops constitutional symptoms and clinically apparent disease, such as opportunistic infections or neoplasms. Higher levels of virus are readily detectable in the plasma during the advanced stages of infection. HIV found in patients with late-stage disease is usually much more virulent and cytopathic than the strains of virus found early in infection. Often, a shift from monocyte-tropic or macrophage-tropic (M-tropic) strains of HIV-1 to lymphocyte tropic (T-tropic) variants accompanies progression to AIDS.

B. CD4 T Lymphocytes, Memory Cells, and Latency

 The cardinal feature of HIV infection is the depletion of T helper-inducer lymphocytes—the result of HIV replication in this population of lymphocytes as well as of the death of uninfected T cells by indirect mechanisms. The T cells express the CD4 phenotypic marker on their surface. The CD4 molecule is the major receptor for HIV; it has a high affinity for the viral envelope. The HIV coreceptor on lymphocytes is the CXCR4 chemokine receptor.

Early in infection, primary HIV isolates are M-tropic. However, all strains of HIV infect primary CD4 T lymphocytes (but not immortalized T-cell lines in vitro). As the infection progresses, the dominant M-tropic viruses are replaced by T-tropic viruses. Laboratory adaptation of these primary isolates in immortalized T-cell lines results in loss of ability to infect monocytes and macrophages.

The consequences of CD4 T-cell dysfunction caused by HIV infection are devastating because the CD4 T lymphocyte plays a critical role in the human immune response. It is responsible directly or indirectly for induction of a wide array of lymphoid and nonlymphoid cell functions. These effects include activation of macrophages; induction of functions of cytotoxic T cells, natural killer (NK) cells, and B cells; and secretion of a variety of soluble factors that induce growth and differentiation of lymphoid cells and affect hematopoietic cells.

At any given time, only a small fraction of CD4 T cells are productively infected. Many infected T cells are killed, but a fraction survives and reverts to a resting memory state. There is little or no virus gene expression in the memory cells, but they provide a long-term, stable latent reservoir for the virus. Less than 1 cell per million resting CD4 T cells harbors latent HIV-1 provirus in patients on successful antiretroviral therapy. Even after 10 years of treatment, patients show very little change in the size of the latent HIV reservoir because the latent reservoir of infected memory cells decays very slowly. When exposed to antigen or when drug therapy is discontinued, the memory cells become activated and release infectious virus. It is possible that other drug-insensitive reservoirs exist among macrophages, hematopoietic stem cells, or brain cells.

It is unlikely that an HIV infection can be cured with standard therapy; if there were a million infected memory cells in the body, it would take about 70 years for them to decay. There has been a recent report of an apparent cure. An HIV-infected man in Germany developed acute myeloid leukemia that necessitated a bone marrow transplant in 2007. After ablation of the patient’s immune system, he was transplanted with cells from a donor homozygous for a CCR5 mutation that protects against HIV infection. The patient stopped taking antiretroviral drugs and remained free of detectable HIV. This success has prompted research to develop ways to purge the latently infected reservoirs in HIV-infected individuals.

C. Monocytes and Macrophages

Monocytes and macrophages play a major role in the dissemination and pathogenesis of HIV infection. Certain subsets of monocytes express the CD4 surface antigen and therefore bind to the envelope of HIV. The HIV coreceptor on monocytes and macrophages is the CCR5 chemokine receptor. In the brain, the major cell types infected with HIV appear to be the monocytes and macrophages, and this may have important consequences for the development of neuropsychiatric manifestations associated with HIV infection.

Macrophage-tropic strains of HIV predominate early after infection, and these strains are responsible for initial infections even when the transmitting source contains both M-tropic and T-tropic viruses.

It is believed that monocytes and macrophages serve as major reservoirs for HIV in the body. Unlike the CD4 T lymphocyte, the monocyte is relatively refractory to the cytopathic effects of HIV so that the virus not only can survive in this cell but can also be transported to various organs in the body (such as the lungs and brain). Infected macrophages may continue to produce virus for a long period of time.

D. Lymphoid Organs

 Lymphoid organs play a central role in HIV infection. Lymphocytes in the peripheral blood represent only about 2% of the total lymphocyte pool, the remainder being located chiefly in lymphoid organs. It is in the lymphoid organs that specific immune responses are generated. The network of follicular dendritic cells in the germinal centers of lymph nodes traps antigens and stimulates an immune response. Throughout the course of untreated infection—even during the stage of clinical latency—HIV is actively replicating in lymphoid tissues. The microenvironment of the lymph node is ideal for the establishment and spread of HIV infection. Cytokines are released, activating a large pool of CD4 T cells that are highly susceptible to HIV infection. As the late stages of HIV disease progress, the architecture of the lymph nodes becomes disrupted.

E. Viral Coinfections

Activation signals are required for the establishment of a productive HIV infection. In the HIV-infected individual, a wide range of in vivo antigenic stimuli seem to serve as cellular activators. For example, active infection by Mycobacterium tuberculosis substantially increases plasma viremia. The damaging effects of HIV on the immune system leave patients vulnerable to many types of infection. The World Health Organization reports that infection with HIV increases the risk of getting tuberculosis as much as 20-fold. Of the 9 million new tuberculosis cases worldwide in 2007, it is estimated that 15% occurred in persons infected with HIV.

Other concomitant viral infections—with Epstein-Barr virus, cytomegalovirus, herpes simplex virus, or hepatitis B virus—may serve as cofactors of AIDS. Hepatitis C virus coinfection, which occurs in 15–30% of HIV cases in the United States and often results in liver disease, is a leading cause of morbidity and mortality in HIV-infected persons. There is also a high prevalence of cytomegalovirus infection in HIV positive individuals.

Coinfections with two different strains of HIV can occur. There are documented cases of superinfection with a second strain in an HIV-infected individual, even in the presence of a strong CD8 T-cell response to the first strain. HIV superinfection is considered to be a rare event.

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المزيد

مواضيع ذات صلة

HIV Infections in Humans: Laboratory Diagnosis

HIV Infections in Humans :Clinical Findings

Animal Lentivirus Systems

Classification of Lentiviruses

Viral DNA Is Integrated into the Host-Cell Genome in Some Nonlytic Viral Growth Cycles

Lytic Viral Growth Cycles Lead to Death of Host Cells

Viral Capsids Are Regular Arrays of One or a Few Types of Protein

Structure and Composition of Lentiviruses

HERPESVIRUSES

POLYOMAVIRUSES

Human T-Lymphotropic Viruses

Replication of Retroviruses