Introduction: HIV stands for human immunodeficiency virus. It is the virus that can lead to acquired immunodeficiency syndrome, or AIDS, if not treated. HIV is a virus spread through certain body fluids that attacks the body’s immune system, specifically the CD4 cells, often called T cells. Over time, HIV can destroy so many of these cells that the body can’t fight off infections and disease. These special cells help the immune system fight off infections. Untreated, HIV reduces the number of CD4 cells (T cells) in the body. This damage to the immune system makes it harder and harder for the body to fight off infections and some other diseases. Opportunistic infections or cancers take advantage of a very weak immune system and signal that the person has AIDS. Learn more about the stages of HIV and how to know whether you’re infected. No effective cure currently exists, but with proper medical care, HIV can be controlled. The medicine used to treat HIV is called antiretroviral therapy or ART. If taken the right way, every day, this medicine can dramatically prolong the lives of many people infected with HIV, keep them healthy, and greatly lower their chance of infecting others. Before the introduction of ART in the mid-1990s, people with HIV could progress to AIDS in just a few years. Today, someone diagnosed with HIV and treated before the disease is far advanced can live nearly as long as someone who does not have HIV. The morphologic structure of HIV-1 HIV-1 viral particles have a diameter of 100 nm and are surrounded by a lipoprotein membrane. Each viral particle contains 72 glycoprotein complexes, which are integrated into this lipid membrane, and are each composed of trimers of an external glycoprotein gp120 and a transmembrane spanning protein gp41. The bonding between gp120 and gp41 is only loose and therefore gp120 may be shed spontaneously within the local environment. Glycoprotein gp120 can be detected in the serum as well as within the lymphatic tissue of HIV-infected patients. During the process of budding, the virus may also incorporate different host proteins from the membrane of the host cell into its lipoprotein layer, such as HLA class I and II proteins, or adhesion proteins such as ICAM-1 that may facilitate adhesion to other target cells. The matrix protein p17 is anchored to the inside of the viral lipoprotein membrane. The p24 core antigen contains two copies of HIV-1 RNA. The HIV-1 RNA is part of a protein-nucleic acid complex, which is composed of the nucleoprotein p7 and the reverse transcriptase p66 (RT). The viral particle contains all the enzymatic equipment that is necessary for replication: a reverse transcriptase (RT), an integrase p32 and a protease p11 (Gelderbloom 1993) life cycle and general mechanism of HIV The seven stages of the HIV life cycle are: 1) binding, 2) fusion, 3) reverse transcription, 4) integration, 5) replication, 6) assembly, and 7) budding. 1- Binding: HIV binds to receptor on the surface of T-cell 2- Fusion: the HIV viral envelope fuses with the CD4 cell membrane. Fusion allows HIV to enter the CD4 cell - the virus releases HIV RNA and HIV enzymes, such as reverse transcriptase and integrase 3- Reverse Transcription: inside a CD4 cell, HIV releases and uses reverse transcriptase (an HIV enzyme) to convert its genetic material—HIV RNA—into HIV DNA. The conversion of HIV RNA to HIV DNA allows HIV to enter the CD4 cell nucleus and combine with the cell’s genetic material—cell DNA. 4- Integration: Once inside the host CD4 cell nucleus, HIV releases integrase, an HIV enzyme. HIV uses integrase to insert (integrate) its viral DNA into the DNA of the host cell. 5- Replication: Once HIV is integrated into the host CD4 cell DNA, the virus begins to use the machinery of the CD4 cell to create long chains of HIV proteins. The protein chains are the building blocks for more HIV. 6- Assembly: During assembly, new HIV RNA and HIV proteins made by the host CD4 cell move to the surface of the cell and assemble into immature (noninfectious) HIV. 7- Budding.During budding, immature (noninfectious) HIV pushes itself out of the host CD4 cell. (Noninfectious HIV can't infect another CD4 cell.) Once outside the CD4 cell, the new HIV releases protease, an HIV enzyme. Protease acts to break up the long protein chains that form the noninfectious virus. The smaller HIV proteins combine to form mature, infectious HIV. Untreated HIV-1 infection is associated with a gradual loss of peripheral CD4+ T cells. Although the direct cytopathic effect of HIV-1 on CD4+ T cells almost certainly contributes to this gradual depletion, most cells destined to die in vivo as a consequence of HIV infection are not productively infected with HIV. This observation has led to the hypothesis that progressive CD4+ T-cell depletion occurs due to indirect effects of viral replication.The mechanism for these indirect effects of HIV replication on CD4+ T-cell depletion is not understood. One widely accepted model postulates that HIV causes accelerated proliferation, expansion, and death of T cells, and that this heightened T-cell turnover eventually results in depletion or exhaustion of the regenerative capacity of the immune system. Multiple studies have shown that HIV infection results in a state of high T-cell turnover (ie, the rates of T-cell proliferation and death are increased). For example, in vivo labeling of T cells indicates that HIV infection results in increased numbers of rapidly cycling CD4+ and CD8+ T cells. These cells are primarily of memory-effector phenotype, and are destined to proliferate and die rapidly. The rate at which HIV recruits cells into this rapid turnover state is directly proportional to the level of viremia,which in turn is directly related to the rate at which CD4+ T cells are lost. In the absence of antiretroviral treatment, markers of Tcell activation and T-cell turnover predict the rate of disease progression and the rate of CD4+ T-cell loss. When antiretroviral therapy is initiated, the rate of T-cell turnover and the degree of generalized T-cell activation both decrease, suggesting that viral replication directly contributes to heightened levels of T-cell activation. Collectively, these observations support the hypothesis that HIV causes disease progression as a consequence of generalized T-cell activation, and that continuous high turnover of T cells—coupled to a suppressed ability of the immune system to regenerate new progenitor T cells—eventually results in gradual loss of peripheral CD4+ T cells. Several immunophenotypic and serum markers have been used to quantify the level of T-cell activation in vivo, including CD38, HLA-DR, CD25, CD69, CD70, neopterin, tumor necrosis factor receptor type II, and β2microglobulin. Of these, the best characterized marker of immune activation has been CD38 expression on T cells; at least one study has shown that CD38 expression on CD8+ T cells had stronger prognostic significance than other commonly used markers of activation. CD38 is a multifunctional transmembrane glycoprotein that is up-regulated during the earliest stages of T-cell activation. Physiologically, CD38 expression and/or ligation has been associated with increased cell-to-cell adhesion, increased levels of cytokine production,and more rapid CD4+ T-cell proliferation. In addition, CD38 expression on T cells is strongly correlated with other markers of cellular activation. The prognostic significance of CD38 appears to be greater when measured based on the mean density per cell rather than the proportion of cells expressing CD38, although this has not been fully addressed in prospective studies. Despite a large number of studies focusing on the relationship between T-cell activation and outcome, only a few have elucidated this relationship over time during primary and early infection. This is surprising since the immunologic and virologic events that occur during the earliest stages of infection can have a strong impact on subsequent disease progression. They therefore assessed the effects of T-cell activation and plasma HIV RNA levels on CD4+ T-cell changes over time in a prospective cohort of acutely and recently HIV-infected adults. Their primary objective was to determine the relative contributions of viremia and T-cell activation to the rate of CD4+ T-cell loss. Their secondary objective was to describe the natural history of activation during untreated HIV infection, focusing on the unresolved question of whether activation reaches a steady state or continually increases over time. Although the role of immune activation in HIV disease pathogenesis has been extensively evaluated in chronically infected patients, its role in primary infection remains poorly defined. Using the density of CD38 expression on T cells as a measure of T-cell activation, they assessed the role of immune activation on disease outcome in acutely and recently infected adults, and have made a number of observations. First, there is a strong and consistent relationship between the level of viremia and the level of both CD4 and CD8 T-cell activation during acute HIV infection. Second, most untreated patients reach a steady-state level of T-cell activation in early HIV infection. This immunologic activation "Set point" varies widely between individuals but is generally stable within a given individual. Third, the CD8 T-cell activation set point during untreated HIV infection is a strong independent predictor of the rate of CD4 T-cell decline. Fourth, initiation of antiretroviral therapy during early HIV infection dramatically reduces the level of CD8 T-cell activation. Collectively, these data support the concept that the pathogenic potential of HIV in a given individual is determined both by the level of viral replication and by the ability of a given virus in a given host to cause sustained increases in CD8 T-cell activation. Most studies suggest that early infection is marked by the establishment of a relative steady-state level of viremia. Importantly, these data also suggest that an immunologic activation set point is established during early infection. This immunologic activation set point was negatively correlated with the viral load set point, suggesting that either the level of viremia in part determined the T-cell activation set point or that the level of T-cell activation determined the viral load set point.The strong association between T-cell activation and CD4 T-cell decline among patients with antiretroviral-untreated HIV infection suggests that the in vivo pathogenicity of HIV in an individual host is determined in part by the ability of that virus to cause heightened immune activation. Simian immunodeficiency virus infection of the sooty-mangabey and the macaque are associated with highlevel viral replication and rapid killing of infected CD4 T cells.Whereas SIV-infected macaques-like HIV-infected humans-exhibit high-level immune activation and progressive immunodeficiency, SIV-infected sooty mangabeys exhibit no consistent increase in immune activation and rarely exhibit evidence of progressive immunodeficiency. Constitutive expression of CD70 in transgenic mice results in chronic T-cell activation, progressive loss of memory and naive T cells, and the eventual development of an AIDS-like syndrome.Finally, this group has recently assessed the role of monocyte/macrophage activation in recently infected individuals initiating highly active antiretroviral therapy.Heightened peripheral blood monocyte activation was strongly associated with low CD4 T-cell counts before and during antiretroviral treatment. These observations, plus other observations made in patients infected with either HIV-2 or drug-resistant HIV-1,36,45-47 clearly point to immune activation as a critical step in the HIV-mediated immunopathogenesis. The mechanisms underlying CD4+ T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. he depletion of CD4+ T cells, the hallmark of HIV-1 infection, has largely been studied in the most accessible compartment, peripheral blood, to understand the mechanisms of this depletion, follow progression of infection, and determine the time to initiate antiretroviral therapy . However, for the reasons outlined below, we believe studies of lymphoid tissue are likely to prove more rewarding in an effort to better understand why CD4+ T cells are depleted, and thereby will enable a more rationally timed antiretroviral therapy. First, most CD4+ T cells reside within the gastrointestinal (GI) tract, LNs, and other lymphatic tissues rather than in peripheral blood . Second, there are large numbers of target cells in the GI tract that express CCR5, the HIV coreceptor for entry . Third, lymphoid tissue has been identified as a major site of HIV replication and a reservoir for HIV in vivo (8–15). Indeed, both viral cytopathic effects and CTL killing of infected target cells could contribute to the depletion of CD4+ T cells from lymphoid tissue. In fact, substantial numbers of HIV or simian immunodeficiency (SIV)-specific CD8+ T cells reside within the GI tract of HIV/SIV-infected individuals and there is one report suggesting that LNs contain a greater breadth of HIV-specific CD8+ T cells than peripheral blood . The relationship between infection of target cells and the cellular immune response is not clear, but it is known that host defenses do not prevent the nearly complete depletion of CD4+ T cells in the GI tract of SIV-infected macaques as early as 2 wk after infection , or the loss of intestinal CD4+ T cells from the early to later stages of HIV-1 infection . Such lymphoid tissues are also likely to play an important role in the maintenance of CD4 T cell numbers throughout HIV infection. Indeed, the fibrosis and architectural disorganization documented in LN biopsies from HIV-infected individuals, which may reflect chronic inflammatory responses associated with viral replication, are likely to affect CD4+ T cell homeostasis. This is underscored by the highly significant correlation between collagen deposition, CD4+ T cell depletion , and CD4+ T cell repletion (unpublished data) on antiretroviral therapy. Collectively, these studies suggest that a full understanding of the mechanisms relating to CD4+ T cell depletion and disease progression will likely require direct analysis of viral infection, the immune response, immune activation and pathology in lymphoid tissue compartments, and the relationship of the dynamics of infection in lymphoid tissue to peripheral blood. However, to date there have been no studies that directly compare T cell depletion, activation, or phenotypic composition in peripheral blood, LNs, and the GI tract from HIV-infected and -uninfected individuals. Here, they recruited 14 treatment-naive, HIV-infected individuals at different disease stages and 7 HIV-uninfected individuals and sampled inguinal LNs, ileal Peyer's patches and lamina propria, and venous blood. From each subject and within each compartment they examined (a) CD4+ T cell depletion; (b) relative levels of naive, effector–memory and central memory CD4+ and CD8+ T cells; (c) T cell activation based upon CCR5 and Ki67 expression; (d) the magnitude of HIV-specific CD4+ and CD8+ T cell responses; and (e) LN collagen composition. Taken together, our data reveal fundamental mechanisms underlying T cell depletion and disease progression in HIV-infected individuals. Much that is understood regarding CD4+ T cell depletion, heightened T cell activation states, T cell dynamics, and HIV-specific T cells in HIV infection is derived from the analysis of peripheral blood lymphocytes. From this current study, the following five major points emerged: (a) the GI tract has the most substantial CD4+ T cell depletion at all stages of HIV disease; (b) this depletion occurs preferentially within the CCR5+ CD4+ T cell subset, which accounts for the majority of GI tract CD4+ T cells; (c) HIV-associated immune activation results in an accumulation of effector/TEM cells within LNs; (d) HIV-specific T cells residing in LNs do not, alone, account for the inflammatory T cell response within HIV-infected LNs; and (e) T cell activation in LNs is associated with collagen deposition Measurement of CCR5+ CD4+ and CD8+ T cells, endoscopic and histological examination of the GI tract, and measurement of activated T cells in each compartment suggested that the GI tract was significantly depleted of CD4+ T cells compared with either peripheral blood or LNs and that this occurred even at very early time points after infection. Ongoing direct infection and sustained death might explain the continued depletion of GI tract CCR5+ CD4+ T cells that is only partially offset by proliferation of CD4+ T cells in the GI tract, and resulting in apparently normal levels of CD4+ T cell activation. The consequence of this would be particularly damaging in the GI tract as, in contrast to LNs, there is only a negligible resident naive CD4+ T cell pool available to become activated, expand, and supply the already profoundly depleted memory CD4+ T cell pool. Alternatively, the decrease in the frequency of CCR5+ CD4+ T cells in the GI tract in HIV infection might arise from altered migration of activated CCR5+ CD4+ T cells into the GI tract, or from recruitment of CCR5 CD4+ and CCR5+ CD8+ T cells to the GI tract. However, the latter explanation requires specific infiltration of two unrelated T cell subsets, CCR5+ CD8+ T cells and CCR5 CD4+ T cells, even though total GI tract lymphoid tissue appears to be dramatically decreased overall. Therefore, they believe the most likely explanation is that direct infection and killing, either by HIV or by HIV-specific T cells, of GI tract CCR5+ CD4+ T cells leads to their profound depletion in acute infection, and that this depletion is maintained during the chronic phase of the disease. Importantly, as the percentage of infected peripheral blood CD4+ T cells is usually