Assessing HIV-1 subtype C infection dynamics, therapeutic responses and reservoir distribution using a humanized mouse model

Snehal Kaginkar ¹ Leila Remling-Mulder ² Ashashree Sahoo ¹ Tejaswini Pandey ¹ Pranay Gurav ¹ Jyoti Sutar ³ Amit Kumar Singh ¹ Ella Barnett ² Sivasankar Panickan ² Ramesh Akkina ^2* Vainav Patel ^1*

• ¹ ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, India
• ² Colorado State University, Fort Collins, Colorado, United States
• ³ Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, India

While HIV-1 subtype C (HIV-1C) is the most prevalent and widely distributed subtype in the HIV pandemic, nearly all current prevention and therapeutic strategies are based on work with the subtype B (HIV-1B). HIV-1C displays distinct genetic and pathogenic features from that of HIV-1B. Thus, treatment approaches developed for HIV-1B need to be suitably optimized for HIV-1C. Here, we demonstrate that humanized mice can be successfully infected with HIV-1C recapitulating disease progression, response to anti-retroviral therapy (ART) and viral rebound following therapy interruption. A limited comparative study with a prototypical subtype B virus was also performed. Viral infection, immune cell dynamics, acquisition of anti-retroviral therapy (ART) resistance and anatomical reservoir distribution following extended and interrupted therapy were compared. We report lower early plasma viremia of HIV-1C, with similar rate of CD4+ T cell depletion compared to HIV-1B. Viral suppression by ART was delayed in the HIV-1C infected group with evidence, in one case, of acquired class wide resistance to integrase inhibitors, a critical component of current global therapy regimens. Also, HIV-1C infected animals displayed faster rebound viremia following ART interruption (ATI). Disparate patterns of tissue proviral DNA distribution were observed following extended ART and ATI suggestive of distinct sources of viral rebound. Results from this preliminary study highlight the utility of the hu-HSC mouse model to address potential differences between HIV-1C and B with implications for prevention, therapeutics and curative strategies.