Breastfeeding transmission accounts for the majority of new pediatric HIV infections and commits infants to lifelong ART, as interruption is typically followed by return of replication and repopulation of reservoirs. Previous studies in adult humans and animal models have identified correlates of viral control following analytical treatment interruption (ATI). However, it is critical to understand the kinetics and predictors of viral rebound in the setting of breastfeeding transmission to inform the development of novel pediatric-focused remission strategies.
At 4 wks of age, Mamu-B*08-/B*17-/A*01- or + rhesus macaques were orally administered SHIV.C.CH505.375H.dCT and placed on daily ART at 2 wpi (Intermediate, n=10) or 8 wpi (Late, n=10). ART was interrupted after 1 yr to assess viral rebound. Blood and lymph nodes (LN) were collected throughout the study for flow cytometry and viral measurements. Spearman correlations were used to identify associations between viral control and over 30 immune parameters measured pre-ATI.
Pre-ATI cell-associated SHIV DNA levels were 14-fold lower in blood (p=0.0003) and 60-fold lower in LN (p=0.0001) in animals that initiated ART earlier in infection, but this did not significantly delay time to viral rebound when compared to animals treated later. In both groups, rebound viremia was detected within 7-35 d post-ATI in all but 1 non-rebounder macaque. Post-treatment control (PTC) of viremia within 98 d of ATI was observed in 9/9 Mamu-A*01+ macaques, an allele known to be associated with CTL responses to an immunodominant Gag epitope. However, PTC was also seen in 5/11 Mamu-A*01- macaques, suggesting viral control could be mediated by other mechanisms. We found that the frequency of Granzyme B+ Ki67+ NK cells (CD3- NKG2A+) in the blood pre-ATI was negatively correlated with area under the curve (AUC) for viral loads during rebound in Mamu-A*01- macaques (r=-0.8424, raw p=0.004). In addition, Mamu-A*01- animals with lower rebound viral load AUC tended to have a higher percentage of anti-Gag IFN-?-producing CD4+ T cells in the blood (r=-0.6126, raw p=0.05) and LN (r=-0.8424, raw p=0.01) prior to ATI.
This work provides novel insight into the predictors of PTC in a preclinical NHP model of pediatric HIV-1 infection. Our findings highlight aspects of innate and adaptive immunity may be critical in controlling viral rebound and should be studied further in the development of remission strategies in HIV-1-infected children.