CD4 Lymphocyte Depletion: Where Have All The Cells Gone?

Hopkins HIV Report 2007 Mar; 19(2):10-12

Scott Kim, M.D. and Joel N. Blankson, M.D.
Johns Hopkins

It has been 21 years since HIV was first isolated and demonstrated to be the cause of AIDS. Progressive CD4 cell depletion has been identified as the fundamental basis of AIDS, but the specific mechanism by which this cell death occurs is still not well understood. It is well accepted that in chronic disease less than 1% of all CD4 cells are infected. The proportional loss of CD4 cells in AIDS far exceeds this prevalence of cell infection, implying that a direct cytopathic effect of the virus cannot be the sole explanation of CD4 cell depletion. In recent years it has been shown that during acute infection there is massive depletion of CD4 cells in the gastrointestinal associated lymphoid tissue (GALT) and other mucosal tissues. Importantly, CD4 cell depletion in these tissues appears to be significantly greater than that observed in peripheral blood.

This important topic stimulated intense discussion at last year’s CROI. In particular, many investigators wondered why this dramatic depletion of GALT CD4 cells was not accompanied by clinical symptoms such as an increase in the incidence of enteric infections. This topic continued to receive a lot of attention this year and data were presented suggesting that depletion of CD4 cells in the gut could in fact have clinical consequences.

Brenchley and colleagues expanded on their prior work on GALT depletion by elaborating a pathophysiologic model by which gut-associated CD4 cell loss in primary infection may be directly responsible for the progressive CD4 cell loss that leads to AIDS [Abstract 65]. They documented high levels of lipopolysaccaride LPS, a component of bacteria cell walls, in the plasma of untreated HIV- infected patients. The levels of LPS in these patients were significantly higher than the levels found in patients on HAART and in HIV-negative patients. The investigators suggested that these high levels of LPS are due to microbial translocation that results from the initial loss of gut-associated lymphocytes. They proposed that this microbial translocation leads to systemic immune activation, as the immune system responds to the potential pathogens crossing the enteric barrier. Activated CD4 lymphocytes recruited to the gut are predisposed to HIV infection and thus affected by direct viral cytotoxicity, preventing any durable repletion of GALT. Systemic immune activation also leads to long-term depletion of CD4 cells in other compartments, by means of deleterious changes in cell homeostasis and life cycle. This cycle of microbial translocation, immune activation, and death of activated lymphocytes contributes to the chronic CD4 cell loss that leads to AIDS.

While this provocative model has received a lot of attention, it is based almost entirely on the elevated LPS levels found in untreated chronically infected patients. Prior studies have demonstrated that LPS may be significantly elevated in disease states like diabetes, in which neither GALT depletion nor significant enteropathy occurs [Creely, et al. Am J Physiol Endocrinol Metab. 2007 Mar;292(3):E740-7.]. Furthermore no direct evidence linking microbial translocation to immune activation was presented. Clearly a lot more work needs to be done in this area.

A separate issue that also received significant attention was the reversibility of HIV-related GALT depletion. Prior investigations had suggested that CD4 cell depletion in gut mucosal tissue occurred within the first several weeks of HIV infection and that significant GALT repletion thereafter was rare, possibly associated with localized control of HIV replication, and unrelated to timing of HAART initiation [Guadalupe M, et al. J Virol. 2006 Aug;80(16):8236-47]. Shenefelt and others presented countervailing data at CROI 2007 to suggest that significant CD4 cell repletion in GALT, in fact, does occur in response to HAART [Abstract 28]. The investigators argued that prior studies had underestimated the CD4 cell population by relying on estimations based on flow cytometry; in this study, they followed absolute cell counts from colonic biopsies in a cohort of 8 patients who started HAART. By cellular staining of tissue sections and immunofluorescent microscopy, they estimated that by 24 weeks of HAART, the GALT CD4 cell population had been reconstituted to 52% of normal levels, while peripheral blood CD4 cells had only increased to 19% of normal levels. Additionally, they reported evidence of lymphoid aggregate reconstitution as well, which had not previously been observed. Further reconstitution between 24-48 weeks after HAART initiation was not observed, suggesting that the benefit of HAART was largely achieved in the first 24 weeks of treatment. A shortcoming of the study was the lack of flow cytometry experiments, which would have provided a basis for comparison between their data and seemingly opposing data from prior investigations.

Other investigators have turned to animal models to more closely investigate the mechanisms involved in CD4 cell depletion. Mario Roederer and colleagues inoculated rhesus macaques with SIV and showed that memory CD4 cells are infected to a much higher extent than naïve CD4 cells [Abstract 95]. By 14 days after infection, approximately 80% of these cells are deleted in the GALT and other mucosal tissue, and PCR analysis suggests that direct infection can explain this massive CD4 depletion. Thus, in contrast to chronic infection, where the cytopathic effect of infection alone cannot explain the progressive CD4 loss, it appears that in primary infection, the majority of CD4 cells die as a direct consequence of infection. In this model the degree of CD4 cell depletion in primary infection was highly correlated with progression to death. Interestingly, a vaccine that markedly reduced viral replication in primary infection also reduced the number of cells that were lost.

In a plenary session, Louis Picker gave a detailed total body analysis of CD4 cell depletion after SIV infection of rhesus macaques [Abstract 14]. Radioisotope labeling demonstrated a high turnover of both CD4 and CD8 cells in infected monkeys. Since CD8 cells are not infected, it is likely that immune activation is the cause of the high turnover of both cell types in chronic infection. He described two distinct types of memory CD4 cells, central memory cells that are capable of proliferative renewal and effector memory CD4 cells that are more differentiated and less capable of proliferation. The effector memory cells are infected very efficiently, but homeostasis is maintained through proliferation of central memory cells, which differentiate into effector memory cells. The infection rate of central memory CD4 is low, but eventual depletion of these cells occurs, leading to insufficient effector memory cell production and AIDS. Picker proposed that AIDS may be best considered as a disease that results from a failure of central memory CD4 cell homeostasis.

CD4 cell depletion is a fascinating topic that clearly needs further exploration. The results of the studies presented have major implications for the decision of when to initiate HAART. In macaques, the degree of CD4 depletion in primary infection correlates with mortality. If this is also true for HIV infection, then it may make sense to initiate HAART during primary infection to preserve these cells where possible. However, if treatment with HAART during chronic infection can in fact lead to the replenishment of CD4 cells in mucosal tissue, then treatment during primary infection may not be beneficial. It will also be very important to confirm the hypothesis that CD4 depletion leads to microbial translocation, as this may be another reason to start therapy early.

2007-01-10
HHR-2007-03-04

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