Rapid progression to human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS) correlates with variation in viral ‘tat’ sequences

Abstract

Mary Bridget Nanteza, David Yirrell1,5, Benon Biryahwaho, Natasha Larke, Emily Webb. Frances Gotch and Pontiano Kaleebu

Gene sequence diversity plays an important function in determining survival of micro-organisms. Pathogenicity of HIV is correlated to host as well as viral factors. We aimed to identify sequence variations in tat, nef and the membrane-proximal gp41. These genes regulate important viral functions: tat for trans-activation, nef for enhancing infectivity and the membrane-proximal gp41 for fusion which could correlate with HIV disease progression. We studied HIV sequences from ART naïve adult Ugandans. Sequence diversity was analysed for 19 rapid progressors and 22 long-term survivors, Rapid progressors were individuals who progressed to a CD4 count of <200 cells/µl in a median time of 3.7 (range 1.3 to 4.9) years. The median time is calculated as being from mid-way between the last HIV sero-negative result and the index HIV sero-positive result, to the time of obtaining the study blood sample. Long-term survivors were individuals who had a CD4 count of >500 cells/µl after a median time of 8.8 (range 7.5 to 9.3) years, measured from the time of the index HIV sero-positive result to the time of obtaining the study blood sample. Amplification of DNA by polymerase chain reaction (PCR) and subsequent sequencing of tat, nef and membrane-proximal gp41 was performed starting from viral DNA directly obtained from frozen uncultured peripheral blood mononuclear cells. A ‘long’ tat protein was only observed in rapid progressors (RPs). The ‘long’ tat appears to predict rapid disease progression and could be relevant for designing an HIV-1 prognostic assay.