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

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.

List of scientific papers

I. Naluyima P, Eller LA, Ouma BJ, Kyabaggu D, Kataaha P, Guwatudde D, Kibuuka H, Wabwire-Mangen F, Robb ML, Michael NL, de Souza MS, Sandberg JK, Eller MA. Sex and Urbanicity Contribute to Variation in Lymphocyte Distribution across Ugandan Populations. PLoS One. 2016 Jan 5;11(1):e0146196.
https://doi.org/10.1371/journal.pone.0146196

II. Flach B, Naluyima P, Blom K, Gonzalez VD, Eller LA, Laeyendecker O, Quinn TC, Serwadda D, Sewankambo NK, Wawer MJ, Gray RH, Michael NL, Wabwire-Mangen F, Robb ML, Eller MA, Sandberg JK. Differential loss of invariant natural killer T cells and FoxP3⁺ regulatory T cells in HIV-1 subtype A and subtype D infections. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):289-93.
https://doi.org/10.1097/QAI.0b013e31828b2073

III. Naluyima P, Eller MA, Laeyendecker O, Quinn TC, Serwadda D, Sewankambo NK, Gray RH, Michael NL, Wabwire-Mangen F, Robb ML, Sandberg JK. Impaired natural killer cell responses are associated with loss of the highly activated NKG2A(+)CD57(+)CD56(dim) subset in HIV-1 subtype D infection in Uganda. AIDS. 2014 Jun 1;28(9):1273-8.
https://doi.org/10.1097/QAD.0000000000000286

IV. Naluyima P, Lal KG, Costanzo MC, Kijak GH, Gonzalez VD, Blom KG, Eller LA, Creegan M, Hong T, Quinn TC, Björkström NK, Ljunggren HG, Serwadda DM, Katabira ET, Sewankambo NK, Gray RH, Baeten JM, Michael NL, Wabwire-Mangen F, Robb ML, Bolton DL, Sandberg JK, and Eller MA. Terminal effector CD8 T cells defined by an IKZF2+KLRF1+IL7R- transcriptional signature expand in HIV infection and mediate potent HIV-specific ADCC. [Manuscript]

V. Olwenyi OA, Naluyima P, Cham F, Quinn TC, Serwadda D, Sewankambo NK, Gray RH, Sandberg JK, Michael NL, Wabwire-Mangen F, Robb ML, Eller MA. Differential Associations of Interleukin 6 and Intestinal Fatty AcidBinding Protein With Progressive Untreated HIV-1 Infection in Rakai, Uganda. J Acquir Immune Defic Syndr. 2016 May 1;72(1):15-20.
https://doi.org/10.1097/QAI.0000000000000915