Publications

The pathogenesis of human and simian immunodeficiency viruses is characterized by CD4(+) T cell depletion and chronic T cell activation, leading ultimately to AIDS. CD4(+) T helper (T(H)) cells provide protective immunity and immune regulation through different immune cell functional subsets, including T(H)1, T(H)2, T regulatory (T(reg)), and interleukin-17 (IL-17)-secreting T(H)17 cells. Because IL-17 can enhance host defenses against microbial agents, thus maintaining the integrity of the mucosal barrier, loss of T(H)17 cells may foster microbial translocation and sustained inflammation. Here, we study HIV-seropositive subjects and find that progressive disease is associated with the loss of T(H)17 cells and a reciprocal increase in the fraction of the immunosuppressive T(reg) cells both in peripheral blood and in rectosigmoid biopsies. The loss of T(H)17/T(reg) balance is associated with induction of indoleamine 2,3-dioxygenase 1 (IDO1) by myeloid antigen-presenting dendritic cells and with increased plasma concentration of microbial products. In vitro, the loss of T(H)17/T(reg) balance is mediated directly by the proximal tryptophan catabolite from IDO metabolism, 3-hydroxyanthranilic acid. We postulate that induction of IDO may represent a critical initiating event that results in inversion of the T(H)17/T(reg) balance and in the consequent maintenance of a chronic inflammatory state in progressive HIV disease.

BACKGROUND

A subset of HIV-infected patients, termed 'elite' viral controllers, maintain undetectable plasma HIV RNA levels in the absence of therapy. In this group, host-mediated viral control may be accompanied by chronic systemic inflammation. It is unknown whether either infection or chronic inflammation is present within the central nervous system of these individuals.

METHODS

Cross-sectional analysis compared cerebrospinal fluid (CSF) HIV RNA and biomarkers of intrathecal inflammation in eight controllers (plasma HIV RNA levels <50 copies/ml) with 26 HIV-uninfected individuals, 25 untreated individuals HIV-infected, viremic individuals, and 23 HIV-infected individuals with treatment-mediated viral suppression (plasma HIV RNA levels <50 copies/ml).

RESULTS

All controllers had CSF HIV RNA levels below 2.5 copies/ml. CSF white blood cell (WBC) counts and CSF: plasma albumin ratios in the controllers were similar to those in both HIV-uninfected individuals and antiretroviral therapy-suppressed HIV-infected individuals. CSF neopterin, MCP-1, and IP-10 concentrations were also not different in the controllers from either HIV-uninfected or treated HIV-infected individuals.

CONCLUSION

The character of CSF HIV infection and degree of immunoactivation in controllers is comparable to that of HIV-uninfected and antiretroviral therapy-suppressed HIV-infected individuals, but distinct from that of untreated, viremic HIV-infected individuals.

PURPOSE OF REVIEW

The purpose of this review is to discuss the apparent impact of persistent-immune activation and inflammation on morbidity and mortality among treated HIV-infected individuals, to explore the potential role of Th17 T-cell depletion in this process, and to discuss potential-therapeutic implications.

RECENT FINDINGS

Although the vast majority of HIV-infected individuals can now achieve and maintain viral suppression with modern-antiretroviral therapy (ART), their life expectancy remains much shorter than the general population and they continue to be at much higher risk for non-AIDS-associated diseases commonly associated with aging (non-AIDS-associated cancer, cardiovascular disease, etc). Abnormal levels of immune activation and inflammation persist despite sustained viral suppression and may drive these clinical events. Although the causes of persistent-immune activation remain incompletely characterized, persistent low-level HIV replication and/or release from latently infected cells in gut-associated lymphoid tissue (GALT) and microbial translocation probably play a major role. Failure to restore Th17 cells in GALT during ART might impair both the recovery of the gut mucosal barrier and the clearance of microbial products.

SUMMARY

Insights from recent-pathogenesis studies might suggest novel-therapeutic approaches designed to restore Th17 cells in GALT, thereby decreasing microbial translocation, immune activation, and ultimately morbidity and mortality during treated HIV infection.

Chronic immune activation and inflammation (e.g., as manifest by production of type I interferons) are major determinants of disease progression in primate lentivirus infections. To investigate the impact of such activation on intrathymic T-cell production, we studied infection of the human thymus implants of SCID-hu Thy/Liv mice with X4 and R5 HIV. X4 HIV was observed to infect CD3(-)CD4(+)CD8(-)CXCR4(+)CCR5(-) intrathymic T-cell progenitors (ITTP) and to abrogate thymopoiesis. R5 HIV, by contrast, first established a nonpathogenic infection of thymic macrophages and then, after many weeks, began to replicate in ITTP. We demonstrate here that the tropism of R5 HIV is expanded and pathogenicity enhanced by upregulation of CCR5 on these key T-cell progenitors. Such CCR5 induction was mediated by interferon-alpha (IFN-alpha) in both thymic organ cultures and in SCID-hu mice, and antibody neutralization of IFN-alpha in R5 HIV-infected SCID-hu mice inhibited both CCR5 upregulation and infection of the T-cell progenitors. These observations suggest a mechanism by which IFN-alpha production may paradoxically expand the tropism of R5 HIV and, in so doing, accelerate disease progression.

HIV "controllers" are persons infected with human immunodeficiency virus, type I (HIV) who maintain long-term control of viremia without antiviral therapy and who usually do not develop the acquired immune deficiency syndrome (AIDS). In this study, we have correlated results from polychromatic flow cytometry and oligonucleotide expression arrays to characterize the mucosal immune responses of these subjects in relation to untreated HIV(+) persons with high viral loads and progressive disease ("noncontrollers"). Paired peripheral blood and rectosigmoid biopsies were analyzed from 9 controllers and 11 noncontrollers. Several cellular immune parameters were found to be concordant between the 2 compartments. Compared with noncontrollers, the mucosal tissues of controllers had similar levels of effector T cells and fewer regulatory T cells (Tregs). Using principal component analysis to correlate immunologic parameters with gene expression profiles, transcripts were identified that accurately distinguished between controllers and noncontrollers. Direct 2-way comparison also revealed genes that are significantly different in their expression between controllers and noncontrollers, all of which had reduced expression in controllers. In addition to providing an approach that integrates flow cytometry datasets with transcriptional profiling analysis, these results underscore the importance of the sustained inflammatory response that attends progressive HIV disease.