Host HLA B*allele-associated multi-clade Gag T-cell recognition correlates with slow HIV-1 disease progression in antiretroviral therapy-naïve Ugandans.
BACKGROUND
Some HIV infected individuals remain asymptomatic for protracted periods of time in the absence of antiretroviral therapy (ART). Virological control, CD4 T cell loss and HIV-specific responses are some of the key interrelated determinants of HIV-1 disease progression. In this study, possible interactions between viral load, CD4 T cell slopes, host genetics and HIV-specific IFN-gamma responses were evaluated in chronically HIV-1-infected adults.


RESULTS
Multilevel regression modeling was used to stratify clade A or D HIV-infected individuals into disease progression groups based on CD4 T cell slopes. ELISpot assays were used to quantify the frequency and magnitude of HIV-induced IFN-gamma responses in 7 defined rapid progressors (RPs) and 14 defined slow progressors (SPs) at a single time point. HLA typing was performed using reference strand conformational analysis (RSCA). Although neither the breadth nor the magnitude of the proteome-wide HIV-specific IFN-gamma response correlated with viral load, slow disease progression was associated with over-representation of host immunogenetic protective HLA B* alleles (10 of 14 SPs compared to 0 of 7; p = 0.004, Fisher's Exact) especially B*57 and B*5801, multiclade Gag T-cell targeting (71%, 10 of 14 SPs compared to 14%, 1 of 7 RPs); p = 0.029, Fisher's Exact test and evident virological control (3.65 compared to 5.46 log10 copies/mL in SPs and RPs respectively); p<0.001, unpaired student's t-test


CONCLUSIONS
These data are consistent with others that associated protection from HIV disease with inherent host HLA B allele-mediated ability to induce broader Gag T-cell targeting coupled with apparent virological control. These immunogenetic features of Gag-specific immune response which could influence disease progression may provide useful insight in future HIV vaccine design.
Serwanga
Jennifer
J
MRC/UVRI Uganda Research Unit on AIDS, c/o Uganda Virus Research Institute, Entebbe, Uganda. jennifer.serwanga@mrcuganda.org
Shafer
Leigh Anne
LA
Pimego
Edward
E
Auma
Betty
B
Watera
Christine
C
Rowland
Samantha
S
Yirrell
David
D
Pala
Pietro
P
Grosskurth
Heiner
H
Whitworth
Jimmy
J
Gotch
Frances
F
Kaleebu
Pontiano
P
D000483:Alleles; D015496:CD4-Positive T-Lymphocytes; D018450:Disease Progression; D015658:HIV Infections / Q000276:immunology / Q000473:pathology*; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014454:Uganda; D019562:Viral Load; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D015235:HLA-B Antigens; D054301:gag Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma