Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection

Abstract

Disease-free infection in HIV-infected adults is associated with HLA-mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of SIV, viral replication continues unabated. To better understand factors preventing HIV disease, we here investigated pediatric infection, where AIDS typically develops more rapidly than in adults. Among 170 non-progressing anti-retroviral therapy-naïve children aged >5yrs maintaining normal-for-age CD4 T-cell counts, immune activation levels were low despite high viremia (median 26,000 copies/ml). Potent, broadly neutralizing antibody responses in the majority of subjects and strong virus-specific T-cell activity were present but did not drive pediatric non-progression. However, reduced CCR5 expression and low HIV infection in long-lived central memory CD4 T-cells were observed in pediatric non-progressors. These children therefore express two cardinal immunological features of non-pathogenic SIV infection in sooty mangabeys - low immune activation despite high viremia and low CCR5 expression on long-lived central memory CD4 T-cells – suggesting closer similarities with non-pathogenetic mechanisms evolved over thousands of years in natural SIV hosts than those operating in HIV-infected adults.

Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals

“…The three VNP individuals described in this study had been infected with HIV-1 for at least 10 years at the time the blood sample was taken, with stable CD4 + T-cell counts and high plasma HIV RNA loads. When compared with three typical (TP) and one rapid progressor (RP) patients, the number of CD4 + T-cells barely declined in the VNPs over this period of time, similar to what have been described for other adult and children VNPs [43, 82–84, 86]. No other significant differences were observed among the VNP and TP patients, including plasma viral load levels and basic virus characteristics such as HIV-1 subtype (all clade B) and coreceptor tropism (all CCR5-tropic viruses).…”

“…Interestingly, viremic pediatric nonprogressor patients with high CD4 + T cell counts seem to be more common than adults VNP individuals [86]. Is it possible that VNP patients are more common than what we originally thought?…”

CXCR6 gene characterization in two ethnically distinct South African populations and association with viraemic disease control in HIV-1-infected black South African individuals

“…Many scenarios of well-controlled infection or disease support a skewing of SIV/HIV infection towards effector memory CD4 + T cells that may be more dispensable, resulting in a more protected CD4 + T cell memory pool. These include non-pathogenic infection of nonhuman primates such as sooty mangabeys and African green monkeys [33], human LTNP/ECs [34, 35], post-treatment controllers [36], and unique groups - adult viraemic nonprogressors [37] and paediatric nonprogressors [38] - who have high viral loads, low immune activation and conserved CD4 + T cell counts. Furthermore, the expression of CXCR6 is critical for antigen-specific memory liver NK cells [39] , and CXCX6 correlates with CD56 expression on T cells which associates with cytotoxic potential [32].…”

The Neutralizing Antibody Response to the HIV-1 Env Protein

“…Of interest, the proportion of chronically infected children who develop broad and potent neutralizing antibodies is considerably higher, with 70% of children mounting responses that are equivalently broad to the top 20% of adults infected with the same subtype of HIV-1 (Fig. 2) [30]. These bNAb responses in children have been reported to develop earlier than is common in adults, in some cases within the first 2 years of life [31, 32].…”

“…These include duration of infection, high viral load, viral diversity and low CD4 T cell counts [26–29, 64]. In children, the high levels of bNAbs are also associated with long-term and high levels of viremia [30]. These associations highlight the substantial antigenic stimulation generally required to drive the high level of somatic hypermutation associated with bNAbs, though there are cases of viral controllers who develop bNAbs [65].…”