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HIV-1 Infections With Multiple Founders Are Associated With Higher Viral Loads
Holly Janes1, Sodsai Tovanabutra2, Joshua Herbeck3, Supachai Rerks-Ngarm4, Merlin L. Robb2, Nelson L. Michael2, Peter Gilbert1, Jerome H. Kim2, Morgane Rolland2
1 Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, United States. 2 US Military HIV Research Program, Silver Spring, MD, United States. 3 University of Washington, Seattle, WA, United States. 4 Thai Ministry of Public Health, Bangkok, Thailand.
Background: A single HIV-1 genetic variant establishes infection in most subjects, including breakthrough infections in the Step/HVTN-502 and RV144 vaccine efficacy trials. We sought to evaluate whether characteristics of the founder viral populations could influence clinical outcomes in the infected participants, specifically whether subjects infected with multiple founder variants would exhibit higher viral loads or lower CD4+ T cell counts.
Methods: HIV-1 breakthrough sequences obtained by single genome amplification from plasma samples collected at diagnosis, and follow up clinical data were available from 63 Step/HVTN502 (MSM infected with HIV-1 subtype B) and 100 RV144 (heterosexuals infected with HIV-1 CRF01_AE) participants. Linear regression models were used to relate qualitative (homogeneous/heterogeneous infection) and quantitative (env diversity measures) viral predictors to clinical post-infection endpoints.
Results: Based on data collected up to 1 year post HIV-1 diagnosis, we found that subjects who had been infected with multiple founder viruses had significantly higher mean viral loads (0.37 log10 higher, p = 0.007 in Step and 0.29 log10 higher, p = 0.024 in RV144). Higher env diversity in the founder population was also associated with higher mean viral load (0.59 log10 higher per 10-fold increase in diversity, p ≤ 0.001 in Step and 0.45 log10 higher per 10-fold increase in diversity, p = 0.011 in RV144). Moreover, in the RV144 cohort, subjects with more diverse HIV-1 founder populations had significantly lower CD4 T cell counts over time (heterogeneity predictor: p = 0.020, env diversity predictor: p = 0.028).
Conclusions: We showed that measures of increased HIV-1 diversity in early HIV-1 infection, both qualitative and quantitative, were associated with markers of poorer clinical outcomes. These results illustrate how consequential the first steps of HIV-1 infection are for clinical disease progression and suggest that limiting the number of viral variants establishing HIV-1 infection may be an important goal for HIV-1 preventive and post-infection disease attenuation strategies.
The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense.