Comparison of viral phenotype and inflammatory biomarker responses in HIV-1 acute subtype A and C infections

Samantha Mcinally^1,2Daniel Claiborne³Elina El-Badry^1,2Rui Xu^1,2Qianhong Qin^1,2Zachary Ende^1,2Martin J Deymier^1,2Jake William Rhodes^1,2Jill Gilmour^4,5William Kilembe⁶Etienne Karita⁷Susan A Allen^1,8Ling Yue^1,2*Eric Hunter^9*

• ¹Emory Vaccine Center, Atlanta, United States
• ²Emory University Emory National Primate Research Center, Atlanta, United States
• ³Wistar Institute, Philadelphia, United States
• ⁴International Aids Vaccine Initiative, New York, United States
• ⁵Imperial College London, London, United Kingdom
• ⁶Center for Family Health Research Zambia, Lusaka, Zambia
• ⁷Center for Family Health Research, Kigali, Rwanda
• ⁸Emory University Department of Pathology and Laboratory Medicine, Atlanta, United States
• ⁹Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States

HIV-1 subtype A and subtype C infections have different rates of clinical disease progression, with subtype C infected individuals in the IAVI Protocol C multisite acute infection cohort having a 60% faster CD4 loss compared to subtype A. In order to investigate whether differences were due to the phenotype of the transmitted founder virus (TFV), or inflammatory cytokines and chemokines, known to drive pathogenesis, we PCR amplified, sequenced and constructed infectious molecular HIV-1 clones from the plasma of 30 acutely infected individuals in Rwanda and Zambia. A comparison of the replicative capacity of 14 subtype A and 16 subtype C TFV showed that they had similar replicative capacity (RC) scores. Nevertheless, high TFV RC scores were linked to more rapid CD4+ T cell loss, and higher inflammatory cytokine levels irrespective of subtype. We next compared the inflammatory plasma cytokine/chemokine profiles of individuals pre-and post-the estimated date of infection of 20 Rwandan individuals infected with subtype A and 34 Zambians infected with subtype C HIV-1. Individuals infected with subtype C exhibited a significant increase in the levels of 10 prominently pro-inflammatory cytokines/chemokines after infection, while, in subtype A infections only 2 cytokines were significantly elevated post-infection. Despite these differences, at 3-months post infection, similar overall biomarker profiles were observed in individuals infected with subtype A or subtype C viruses , primarily due to higher pre-infection baseline biomarker levels in Rwanda. In the combined cohort, we found a highly significant association between faster CD4+ T cell decline and higher levels of ITAC (CXCL11), which in turn was linked to higher TFV RC. This finding suggests that high levels of ITAC during acute HIV-1 infection are a marker for rapid disease progression.