Being that the GI tract is the largest lymphoid organ in the body, it would follow that the potential for deleterious effects of HIV-1 infection would be great at this site. Although the effect of primary HIV-1 infection on lymphocyte populations in the peripheral blood has been well characterized, the events associated with primary HIV-1 infection in GI mucosal lymphocyte populations in man has to date remained largely unknown. Given the strong selection pressure for CCR5 coreceptor using viruses during transmission of HIV-1 (23
), it would be likely that the sizable population of CCR5-expressing, immunologically activated CD4+
T cells in the GI mucosa would be more supportive of viral replication and susceptible to its deleterious effects as compared with the peripheral blood where the T cells are predominantly CCR5−
and naive (8
). We undertook this study to assess whether a preferential depletion of mucosal CD4+
T cells would be observed in primary HIV-1–infected subjects as has been observed in the SIV-macaque model. We went on to examine the anatomic subcompartment from which these cells are depleted and examine whether suppressive HAART therapy could result in complete immune reconstitution in the mucosal compartment.
Previous studies of the effect of HIV-1 on the GI mucosal CD4+
T cells during the primary infection period have been limited to a single report, with two subjects studied during early HIV-1 infection. In both of these individuals, identified after 4 and 6 wk of the estimated date of infection, mucosal CD4+
T cell depletion was noted (19
). The remaining data suggesting the GI tract as the preferred site for virus replication and CD4+
T cell depletion are derived from studies examining primary infection of macaques with SIV (2
Here we have described 13 subjects who are identified and studied extremely early in the course of HIV-1 infection. We have confirmed that indeed, significant mucosal CD4+
T cell depletion occurs in subjects during primary HIV-1 infection, before changes seen in the peripheral blood. However, human mucosal CD4+
T cell depletion appears to be less marked than that described in primary SIV infection, where the percentage of CD4+
T cells in the macaque small bowel was reduced to <10% by 3 wk after infection (13
). This is likely explained by a difference in the site sampled. All the biopsies in our studies were obtained from the rectal mucosa, which has both effector and inductive lymphoid tissue. In the macaque models described, the biopsies are usually obtained from the proximal jejunum, which is devoid of immune inductive sites (26
). As a result, samples obtained from the jejunum in macaque models may demonstrate a much higher degree of CD4+
T cell depletion compared with what is noted in this study. There may also be other factors responsible. SIV is introduced in large inocula to attempt to guarantee infection. Simian AIDS is characterized by an accelerated natural history of the disease (27
) and is accompanied by higher peak plasma viral levels (29
) when compared with HIV-1 infection in man. Also, SIV is known to use alternative and additional coreceptors when compared with HIV-1 (31
), which may account for apparent differences in replication dynamics. Yet unexplained differences may also exist in host susceptibility to the two infections.
In addition to confirming the numerical decrease in mucosal CD4+
T cell percentage, we have gone on to characterize the relationship between CD4+
T cell depletion and HIV-1 RNA localization within specific anatomic subcompartments of the GI mucosa. Like the small intestine, the immune compartment in the rectal mucosa is also divided into inductive and effector arms (24
). The organized lymphoid tissue with a high content of CD68+
MHC class II+
macrophages and cells expressing costimulatory molecules CD86 and CD40 serves as an antigen-presenting site (24
). The majority of lymphocytes present in the inductive compartment are antigen naive. However, once activated and primed by antigen-presenting cells such as dendritic cells, GI mucosal lymphocytes can home back to the mucosa to perform effector functions (34
). The lamina propria lymphocytes, which are comprised of a high percentage of differentiated effector cells (9
), serve as the effector arm of the mucosal immune system (33
). A limited number of studies have described the effects of SIV infection (24
) and chronic and advanced HIV-1 infection (35
) on these distinct, anatomic subcompartments. Our results suggest that as early as the primary infection stage, there is a depletion of CD4+
T cells from the effector compartment of the GI mucosa. Given the activated and differentiated phenotype of these cells, direct cytopathic effects of the HIV-1 virus could be one mechanism explaining this lesion. To assess this, we performed in situ hybridization for HIV-1 RNA to localize the sites of HIV-1 replication in the GI mucosa. We observed that HIV-1 RNA was localized in the inductive compartment of the mucosa. These findings are consistent with the SIV-macaque model where during early infection, most of the SIV-infected cells are located in the inductive sites. In a recent study, Veazey et al. (26
) noted that very early in the course of infection, i.e., from 7 to 14 d after infection, SIV-infected cells could be localized in the effector compartment as well. However, once effector CD4+
T cells were depleted, SIV RNA was predominantly seen in the inductive compartment. Our patients, although studied extremely early in the course of HIV-1 infection, had already developed profound CD4+
T cell depletion in the effector sites. Thus, one possible explanation for the localization of HIV-1 RNA only in the inductive compartment is the loss of target cells from the effector sites by the time the biopsies were performed.
Further studies are underway to better characterize the dynamics of CD4+
T cell loss noted in the effector compartment. Some of the possibilities include decreased local proliferation, increased cell death in the effector compartment due to apoptosis or activation-induced cell death (36
), reduced homing of cells to the effector site from the periphery after antigen recognition due to either direct cytopathic effects of HIV-1 or immune activation-induced cell death, or perhaps combinations of the above (37
By studying subjects in whom treatment was initiated during acute and early HIV-1 infection, we sought to understand whether HAART would result in mucosal CD4+
T cell reconstitution. Guadalupe et al. (19
) showed that in one subject, mucosal CD4+
T cell reconstitution was attained when HAART was initiated within 6 wk of the estimated date of infection. In comparison, we did not see immune reconstitution in the GI mucosa with HAART in our study population. It is to be noted that all eight patients studied initiated therapy in the primary infection stage, remained compliant with treatment, and continued to have undetectable plasma HIV-1 RNA levels for the entire duration of the study period. The cohort remains small and we plan to study more subjects longitudinally to better assess the degree of immune reconstitution and the factors that may predispose to a greater or lesser response.
The consequence of early depletion and incomplete reconstitution of mucosal CD4+ T cells is unclear. Although opportunistic infections remain rare until the peripheral CD4+ T cell count falls during the chronic infection period, the long-term outcome of treated HIV-1 infection remains unknown. Furthermore, the nature of the CD4+ T cell loss requires additional study. Theoretically, the loss of specific clones of CD4+ T cells in the mucosa may predispose to accelerated immune senescence, more rapid than that seen as a consequence of aging, which in turn may result in the increased incidence of malignancies, be they lymphomas or solid tumors such as adenocarcinomas.
Given the importance of the mucosal compartment in HIV-1 pathogenesis, our findings may have important implications with regard to treatment. Perhaps efforts to specifically inhibit T cell activation in the GI tract as well as drugs to more specifically interfere with HIV-1 entry (38
) and replication in the GI mucosa during the primary infection period may result in lowering of the viral set point and in conjunction with HAART, result in improvement in clinical outcome. Such investigations are clearly needed as the goal of optimized treatment of HIV-1 infection is yet to be attained.