Limited Sequence Variation and Similar Phenotypic Characteristics of HIV-1 Subtype C Gag Variants Derived From the Reservoir and Pre-Therapy Plasma

Antiretroviral therapy (ART) reduces HIV viral replication to undetectable levels by standard viral load measurements. However, when antiretroviral therapy is interrupted, HIV replication resumes, revealing that HIV persisted in cellular and anatomical tissues during treatment. These reservoirs can reignite and sustain infection; therefore a viable cure requires that this HIV reservoir is eliminated.   Investigation of whether viral variants present in the reservoir differ from those circulating in peripheral blood prior to treatment initiation, could better inform immune-based interventions for HIV cure.  In this study, viral variants in the peripheral blood and lymph node reservoir were compared to those in pre-therapy plasma, in 24 individuals living with HIV from cohorts in Durban, South Africa.  In particular, the Gag protein of the virus was characterised as it is a major target of therapeutic vaccines and influences replication ability of the virus as well as susceptibility to antiviral cytokines.  Viral characteristics measured included replication capacity, interferon-alpha resistance, cell-to-cell spread ability, and induction of antiviral cytokines, as determined by the viral Gag protein.  Mutations in Gag that result in escape from immune responses were also identified. Results showed limited novel Gag mutations, and a similar extent of immune escape mutations, in the reservoir viral variants compared to the pre-therapy viral variants.  The novel Gag mutations in the reservoir variants did not significantly alter virus characteristics overall, and are therefore unlikely to affect effectiveness of immune-based interventions for virus eradication.