Abbreviations GALT: gut-associated lymphoid tissue; HAART: highly active antiretroviral therapy.
HIV is known to cause multiple effects on the immune system. However, there has been debate as to what the primary in-vivo cellular targets of HIV infection are. One school of thought has focused on activated CD4 T cells in the gut as the primary target of HIV infection whereas another has argued that the target included both resting and activated CD4 T cells, primarily in mucosal tissues. We know from studies in both HIV-infected subjects and SIV-infected animal models that, in addition to mucosal tissues, peripheral tissues are actively involved in acute HIV infection. However, in contrast to mucosal tissues, the analysis of peripheral CD4 T cells are complicated by the heterogeneity of CD4 T cell subsets. Here we review the current paradigms of acute HIV pathogenesis and attempt to put in perspective the observed CD4 T cell dynamics in the mucosa relative to peripheral tissues. We conclude that the primary target of HIV infection is the CD4 memory T cell compartment in all tissues of the body. Furthermore, HIV causes a ‘systemic’ loss of CD4 memory T cells very early during acute infection. The failure of the immune response to control this early infection and destruction eventually lays the groundwork for disease progression and immunodeficiency.
Acute HIV infection causes systemic destruction of CD4 memory T cells
Recent studies [1••,2••] have challenged the long-held view that HIV causes a slow and progressive depletion of CD4 T cells leading to immunodeficiency and AIDS. These studies, using the SIV infection model, demonstrated that HIV pathogenesis can be divided into two major phases of disease: an initial explosive phase of extensive systemic destruction of memory CD4 T cells that is a function of substrate availability and precedes emerging immune responses, followed by a slow and progressive chronic phase that is characterized by chronic immune activation and a gradual loss of remaining CD4 T cells over a period of time. The acute phase is clinically similar to many viral infections; the chronic phase is accompanied by systemic effects such as deterioration of lymph-node architecture, susceptibility to opportunistic infections, and gut-associated and neurological problems.
The causes of eventual immunodeficiency remain controversial. One hypothesis [3,4] links immunodeficiency primarily to the extensive loss of CD4 T cells from gut-associated lymphoid tissues (GALTs). GALTs are thought to harbor the majority of all T cells in the body, and the highly antigenic microenvironment contributes to the enrichment of activated and resting memory T cells in this compartment. In addition, a specific enrichment of activated, CCR5+ memory CD4 T cells makes it an ideal target for HIV viral replication.
Initial reports in the SIV model [5–7] and recently in HIV-infected subjects [8–10] demonstrated the near-complete loss of CD4 T cells from mucosal sites in acute infection. In contrast, these studies reported that peripheral CD4 T cells are largely spared and survived the initial phase of infection. It was hypothesized that these distinct effects are due to the predominantly activated nature of CD4 memory T cells residing in mucosal tissues, and that the primary CD4 T cells lost from the periphery were the mucosal homing T cells.
Nonetheless, other groups reported that most of the CD4 T cells lost very early during infection had a resting memory phenotype (Ki-67− and CD69−) and that these cells could actively support viral infection [2••,11]. It is important to note that most (>95%) of mucosal CD4 T cells are CD45RA− with approximately 30–75% expressing CCR5 in both macaques [1••,12] and humans [8,13,14]. However, the almost total loss of mucosal CD4 T cells during acute infection in both macaques and humans indicates that, in addition to CCR5+ CD4 T cells, CCR5− mucosal CD4 T cells were also lost during acute infection. A productive infection of resting memory CD4 T cells [2••] brings into question the hypothesis that HIV/SIV primarily targets only activated CD4 T cells. Indeed, peripheral tissues such as the spleen and organized lymph nodes (for example, inguinal, axillary and mesenteric lymph nodes) harbor large numbers of memory CD4 T cells that, unlike their mucosal counterparts, have a resting phenotype. Furthermore, there have been no reports showing that memory CD4 T cells isolated from distinct tissue compartments differ in their ability to support viral infection, hence making them preferential targets for infection.
It is important to note that the composition of CD4 T cells in the mucosa and other sites differs dramatically [1••]. CD4 T cells in mucosal tissues are all uniformly memory T cells, whereas peripheral CD4 T cells are a heterogeneous mix of naïve and memory subsets [1••,15]. Thus it is not reasonable to compare total CD4 T cell dynamics in the mucosa with that in the periphery as the variability in naïve CD4 T cell representation may mask the significant loss of memory CD4 T cells. As SIV, and all transmitted variants of HIV, are CCR5-tropic viruses and infect only memory CD4 T cells during primary infection [1••], it is critical that we restrict analysis of acute infection dynamics to solely the subsets capable of expressing CCR5: that is, the memory CD4 T cell subset. Indeed, such an analysis reveals that the catastrophic loss of memory CD4 T cells is not restricted to mucosal tissues alone, but rather occurs in all tissues simultaneously [1••].
The simultaneous loss of memory CD4 T cells in all the tissues also demonstrates that the loss of these cells from the peripheral blood (the most commonly measured parameter of disease) is not due to redistribution. Furthermore, the similar kinetics of peak infection and its resolution in both mucosal and peripheral compartments, independent of the route of infection [1••,2••], indicates that substrate exhaustion observed during the early stages of acute infection is not restricted to mucosal tissues alone but occurs in all the tissue compartments.
In fact, the kinetics of T cell loss reveal that HIV/SIV infections truly are explosive. Whether the virus is introduced mucosally [2••] or intravenously [1••], once infection is established it moves through the entire immune system with great rapidity, depleting CD4 memory T cells (both resting and activated) in every compartment of the body. Nonetheless, the importance of the destruction of the mucosal CD4 compartment cannot be understated: given that these represent a majority of CD4 T cells in the body this insult is massive in terms of both numbers and functional consequence.
Previous studies suggested that the only cells that were lost from both the mucosa and periphery of HIV/SIV infections were CCR5-expressing CD4 T cells . However, unlike the expression of CCR5 on mucosal CD4 T cells, very few peripheral CD4 memory T cells express CCR5. It was a conundrum, then, that the loss of CD4 memory T cells significantly outstripped the apparent expression of the obligate coreceptor CCR5 on memory cells. In fact, our recent studies [1••] illustrated that the primary substrate for HIV replication is the ‘total’ memory CD4 compartment, irrespective of apparent CCR5 expression: cell-associated viral loads were as high in CCR5− memory CD4 T cells as in CCR5+ counterparts.
This conundrum was resolved by showing that ‘CCR5−’ memory T cells actually express CCR5 mRNA and apparently express sufficient protein to render them susceptible to SIV infection, but not sufficient to be measurable by flow-cytometric assays [1••]. This analysis substantiates the conclusion that the ‘total’ CD4 memory compartment is the important parameter for measuring SIV/HIV infection.
Whereas the infection of CD4 memory T cells during the acute phase was sufficiently large to solely account for the destruction of those cells, it is still possible that other mechanisms were playing a role in depleting CD4 cells, as suggested by Li et al. [2••]. In particular, it is still not clear as to what frequency of memory cells that harbored SIV DNA are productively infected. To account for any additional killing (beyond that induced by viral infection), Li et al. [2••] proposed that bystander apoptosis was playing a role in this process. These authors suggested that gp120 binding to uninfected cells might be responsible for their loss. It is possible however that the cells undergoing bystander apoptosis were minimally infected and carried viral DNA.
In any case, we now know that the infection of CD4 T cells during the acute phase is dramatically higher than at any other stage of disease (Fig. 1). This massive infection leads to a destruction of the majority of CD4 memory T cells during the first 2–3 weeks after infection, and undoubtedly becomes the basis for subsequent immunodeficiency.
Unlike acute infection, chronic infection takes place after the extensive loss of available substrates (Fig. 1). What follows is the result of chronic immune activation leading to the shrinking of the naïve CD4 T cell pool and expansion of the memory CD4 T cell subsets that become targets for either direct or indirect killing . Chronic infection is characterized by an extensive turnover of both peripheral CD4 and CD8 T cells leading to a slow and progressive decline of the CD4 T cell pool that ultimately leads to AIDS. In contrast to the periphery, the near-total depletion of CD4 T cells in mucosal tissues is followed by a failure to repopulate during the course of HIV disease, indicating that in the absence of therapy HIV causes a continuous loss of CD4 T cells.
Numerous mechanisms have been proposed for the loss of cells during chronic disease with a primary role for bystander killing, as most of the cells that die are found to be uninfected [17,18], both CD4 and CD8 T cells are rapidly turned over [17–21], and naïve CD8 T cells disappear roughly the same rate as CD4 cells . Studies have shown that in chronic HIV infection the rate of CD4 T cell decline correlates with markers of immune activation [23–25]. The role of immune activation in chronic HIV infection and associated loss of CD4 T cells have been reviewed extensively elsewhere [26,27].
Acute infection and immune responses
The role of immune responses in early viral control has remained controversial. Studies have shown that reduction in acute viremia was associated with the emergence of HIV-/SIV-specific immune responses that were dominated by CD8 T cells [28–31], and CD8-depletion studies demonstrated a critical role played by CD8 T cells in viral control [32–34].
Early reports showed that both GALT and peripheral blood harbored similar frequencies of SIV-gag-specific tetramer responses at 2–3 weeks post-infection [35,36]; however, Vingert et al.  demonstrated that mucosal tissues harbored very low levels of SIV-specific interferon-γ-secreting CD8 T cells during the first 28 days of infection. It should be noted, however, that assays to detect antigen-specific T cells based on a response to ex-vivo stimulation (for example, ELISpot or ICS) are compromised by the fact that the cells, particularly during acute infection and from the gut, are already activated in vivo and may not respond to antigen stimulation.
Interestingly, measurable immune responses invariably emerge ‘after’ the massive destruction of CD4 T cells from various compartments of the body. Recent studies [38•] explored the kinetics of emergence of CD8 T cell responses following vaginal challenge. These studies report that though CD8 responses were observed in vaginal tissues, there was a long lag between their emergence and the peak of infection, and these responses were very weak or undetectable in the GALT. The authors suggested that the inability to clear viral infection is related directly to the lack of a strong immune response in mucosal sites, and concluded that these responses are ‘too little too late’ to prevent infection and the massive loss of CD4 memory T cells. These results suggest strongly that the de-novo-generated adaptive immune response is not the mechanism by which CD4 memory T cells are depleted during acute infection, and largely fail to control the initial explosive-phase of infection as originally proposed by Phillips .
It is critical to recognize the potential impact of the massive destruction of the CD4 memory compartment on the generation and maintenance of CD8 T cell immune responses. The role of CD4 T cell help in the generation of CD8 T cell responses has been clearly demonstrated in other chronic infections, such as lymphocytic choriomeningitis virus. The ability of HIV and SIV to replicate during chronic infection even in the presence of strong and polyclonal CD8 responses as measured by interferon-γ secretion indicates a functional defect in the ability of CD8 T cells to contain viral infection. Hel et al.  demonstrated that though peripheral and mucosal tissues harbored SIV-gag-specific CD8 T cells, the cytolytic potential and their ability to produce interferon-γ or tumor necrosis factor-α were low in peripheral blood and spleen and even lower in mucosal tissues of animals that failed to control viremia. The role that CD4 T cells play in this process has yet to be delineated clearly.
In HIV-1-infected individuals treated early during primary infection the preservation of HIV-1-specific helper CD4 T cell responses was associated with viral control after interruption of antiretroviral therapy . Lichterfeld et al.  demonstrated that CD8 T cells in acute HIV infection had a strong capacity to proliferate, a function that was lost rapidly in the presence of viral replication but partially preserved by antiretroviral therapy. The proliferation of these CD8 T cells depended critically on interleukin-2-secreting, antigen-specific CD4 T cells. The authors concluded that the loss of CD8 function was not due to intrinsic defects but rather due to the loss of HIV-specific CD4 T cells. Similarly it was demonstrated  that restoration of HIV- and Epstein–Barr virus-specific CD8 T cell responses during highly active antiretroviral therapy (HAART) was associated with increased CD4 T cell numbers.
However, recent studies [44,45] in acutely HIV-infected subjects who started HAART early during infection indicate that the mechanisms of viral control may be much more complex than anticipated. These studies showed that four out of five patients on early HAART had higher numbers of interferon-γ- and interleukin-2-secreting CD4 T cells but that these higher responses were not associated with the control of viremia following treatment interruption. Other critical issues such as the time of starting therapy and the extent of preservation in mucosal tissues may play a role. Though limited studies show no beneficial effect of early preservation of CD4 T cells on control of HIV viremia, early preservation of CD4 T cells may have a significant benefit in preventing CD8 dysfunction against various other previously encountered viral pathogens that otherwise contribute to immunodeficiency. And, of course, preservation of CD4 T cells during acute infection may be important for staving off the inevitable immunodeficiency manifest during chronic disease.
Overall, massive systemic destruction of memory CD4 T cells during the early acute phase sets the stage for onset of immunodeficiency by disabling the ability of the immune system to mount secondary immune responses to previously encountered pathogens. The extent of this depletion may predict the progression to AIDS. The delay in the emergence of immune responses would mean that the CD4 memory compartment is doomed from the point of viral infection. However, recent studies by Miller et al. [46•] give hope for devising strategies aimed at effectively controlling infection before it explodes through the CD4 T cell compartment. These studies demonstrated that initial infection was restricted to a small founder population of memory CD4 T cells in mucosal tissues that were infected by days 3–4 postinfection that then spread explosively to other cells by day 10 postinfection, suggesting that a strong and broad pre-existing CD8 T cell response might effectively contain the spread of early infection. Prior vaccination that can induce such strong mucosal immune responses may play a critical role in containing the spread of viral infection. Early containment of viral replication will have a significant impact on viral loads and subsequent transmission of infection. Longitudinal studies of discordant couples show that transmission of HIV was highly unlikely when plasma viral loads were below approximately 2000 copies/ml, and similarly in a study of over 550 mother–child pairs no mother-to-child transmission was observed when maternal viral loads were below 1000 copies/ml [47,48].
Highly active antiretroviral therapy and mucosal repopulation
The massive loss of CD4 T cells during acute HIV infection severely disables the immune system. With the advent of HAART progress has been achieved in repopulating CD4 T cells and maintaining CD4 T cell numbers by controlling viremia, leading to better health and longer life spans. However, the limited data available to date show that HAART is not successful in repopulating mucosal tissues that harbor most of the T cells in the body. Mucosal tissues harbor numerous pathogens, and are the primary site for most secondary infections observed during HIV infection. Hence, a loss of essentially all pre-existing mucosal CD4 T cells compromises the ability of the mucosal immune system to generate secondary immune responses, thereby hastening the onset of immunodeficiency.
Studies using both HIV-infected subjects [9,10] and animal models [6,49] have shown only a partial and transient repopulation of mucosal tissues following antiretroviral therapy. Mehandru et al.  found that in eight HIV-infected subjects who started HAART early during primary infection, therapy failed to significantly repopulate mucosal CD4 T cells. In contrast, Guadalupe et al.  demonstrated that one patient who started HAART within 6 weeks of infection attained significant mucosal repopulation. These studies, along with limited studies using animal models, suggest that there may be a window of opportunity for initiating HAART to preserve mucosal CD4 T cells.
Development of therapeutic approaches to preserve mucosal CD4 T cells will be important to protect the integrity of the mucosal immune system. This may require a shift in strategy, with the focus being on starting early therapy rather than delaying HAART. However, given the side effects and cost of HAART one may need to develop alternate strategies such as therapeutic vaccination and early antiretroviral therapy that can harness the potential of the immune system to control HIV.
The dramatic events observed during acute HIV infection highlights the need for a shift in current strategies of antiretroviral therapy with the focus on early preservation of CD4 memory T cells, and rapid development of vaccines that can contain the spread of viral infection and maintain the integrity of the entire CD4 T cell compartment. These approaches will have a significant impact on delaying disease progression and subsequent immunodeficiency, and thereby decrease morbidity and enhance survival in HIV-infected people.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 89–90).
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