Immunologic, virologic and genetic studies of HIV-1 infected long-term non-progressors in Uganda

HIV -l-specific T -cell responses are preserved in HIV -1 infected individuals with non- progressing HIV -1 disease. Evaluation of HIV -I-specific T -cell functionality; T -cell phenotype; HLA class; subtype, RNA and DNA levels of HIV -1; and other factors in long- term non-progressors (LTNP) in comparison with rapid progressors (RP) could reveal novel correlates of protection against disease progression. We show that HIV -1 RNA viral load, proviral DNA load and lipopolysaccharide (LPS) were positively correlated with each other and negatively correlated with CD4 count. We show that IFN-y Gag-specific responses were higher in LTNP, whereas IFN-y Nef-specific responses were higher in RP. Nef-specific responses positively correlated with HIV-I RNA viral load, proviral DNA load and LPS. Flow cytometric analysis of HIV -l-specific responses showed that IFN -y +, CD I 07 a +IFN -y +, and IFN-y+TNF-a+ dual responses to Gag-p24 were higher in LTNP and correlated positively with CD4 count. Nef-specific responses in LTNP were predominantly polyfunctional. Among HIV-I-specific responses to Gag-pI7, Gag-p24 and Nef, only production of IFN- y+TNF-a+ in response to the Nef-specific pep tides correlated negatively with both RNA viral load and proviral DNA load and was a good correlate of protection. In analysis of perforin and degranulation, Nef-specific responses showed higher monofunctional CD8+CD 1 07a +PF in RP and CD8+CD107a+PF+ in LTNP. CD8+CD107a+PF positively correlated with RNA viral load, proviral DNA load and LPS and negatively correlated with CD4 T-cell count. IL- 21 levels in the CD8 T-cells of RP were higher than in the LTNP. CD4+CD45RA +CD38+HLADR+ T-celllevels, PD-l levels and CD8+ naive T-cells were higher in the LTNP. PD-1 levels and CD8+ naive T-cells correlated negatively with LPS and positively with CD4 count, PD-l also correlated negatively with RNA viral load. High CD8 naive T -cells and PD-I expression were good correlates of protection. T -cell regulatory levels were not significantly different in LTNP and RP. Correlates of rapid disease progression included high IFN-y Nef-specific responses and high monofunctional CD8+CDI07a+PF Nef-specific responses.EThOS - Electronic Theses Online ServiceGBUnited Kingdo