Role of innate cellular immunity in the immunopathogenesis of HIV-1 infection in Uganda

Abstract

The global epidemic of HIV has resulted in more than 34 million deaths and currently 36.9 million HIV-infected people worldwide. Uganda has an HIV prevalence of 7.3%, equating to about 1.6 million people. This has placed enormous pressure on the social, economic and medical structure of society. HIV is phylogenetically diverse, with HIV-1 subtypes A, B and C accounting for ≥70% of infections globally. While HIV-1 subtype C confers the worst prognosis for a patient, it is closely followed by subtype D which, together with subtype A, accounts for ≥90% of HIV infections in Uganda.

HIV infection is associated with rapid viral replication, concomitant inflammation and immune activation, and massive CD4 T cell loss, which all together contribute to morbidity and eventual death. Although antiretroviral therapy lowers viral load and improves CD4 T cell recovery in chronic infection, it does not fully eliminate chronic immune activation nor restore immune function, resulting in non-AIDS related morbidity. Additionally, despite great effort, a preventive or therapeutic vaccine is yet to be developed.

Studies in chronic untreated HIV-1 infection may shed more light on correlates of immune protection that may be utilized to develop effective preventive or therapeutic vaccines or drugs. The innate immune system, as the first to encounter the HIV virus upon exposure and infection may be critical in directing immune responses that can prevent, attenuate or cure infection. In this thesis I aimed to study the role of the innate cellular immunity in the immunopathogenesis of HIV-1 subtype A and D infection in Uganda.

In Paper I, using whole blood from healthy blood bank donors, we established normal lymphocyte reference ranges for Ugandans and showed demographic differences that may influence immune responses to disease and vaccination. Additionally, utilizing cryopreserved peripheral mononuclear blood cells from chronic untreated HIV-1 infected persons we studied the phenotypes and function of natural killer cells, unconventional T cells and regulatory T cells plus their roles in HIV-1 infection (Papers II-IV). Here we found both HIV-associated immune dysregulation of multiple cellular subsets and expansion of a previously little described innate-like terminally differentiated CD8 T cell subset. Furthermore, in Paper V we describe demographic differences in biomarkers of inflammation that not only associate with disease progression, but also expand our knowledge of HIV-related gut dysbiosis. Thus, the data presented here provides more insight into HIV-driven immune dysfunction, subtyperelated immunopathogenesis, and demographic differences that add to the body of knowledge concerning HIV infection.