Evolution of the human immunodeficiency virus type 2 envelope in the first years of infection is associated with the dynamics of the neutralizing antibody response

Abstract

BackgroundDifferently from HIV-1, HIV-2 disease progression usually takes decades without antiretroviral therapy and the majority of HIV-2 infected individuals survive as elite controllers with normal CD4+ T cell counts and low or undetectable plasma viral load. Neutralizing antibodies (Nabs) are thought to play a central role in HIV-2 evolution and pathogenesis. However, the dynamic of the Nab response and resulting HIV-2 escape during acute infection and their impact in HIV-2 evolution and disease progression remain largely unknown. Our objective was to characterize the Nab response and the molecular and phenotypic evolution of HIV-2 in association with Nab escape in the first years of infection in two children infected at birth.ResultsCD4+ T cells decreased from about 50% to below 30% in both children in the first five years of infection and the infecting R5 viruses were replaced by X4 viruses within the same period. With antiretroviral therapy, viral load in child 1 decreased to undetectable levels and CD4+ T cells recovered to normal levels, which have been sustained at least until the age of 12. In contrast, viral load increased in child 2 and she progressed to AIDS and death at age 9. Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous. Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed. Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2. Rates of R5-to-X4 tropism switch, of V1 and V3 sequence diversification, and of convergence of V3 to a β-hairpin structure were related with rate of escape from the neutralizing antibodies.ConclusionOur data suggests that the molecular and phenotypic evolution of the human immunodeficiency virus type 2 envelope are related with the dynamics of the neutralizing antibody response providing further support for a model in which Nabs play an important role in HIV-2 pathogenesis.

Evolution of HIV-1 within untreated individuals and at the population scale in Uganda

“…Together with the observation that within-host viral lineages leading to transmission events evolve approximately half as fast as other lineages [ 7 ], these findings build a consistent picture of different rates of evolution for HIV-1 within- and between-hosts, for all of the subtypes that have been analyzed, and across the whole genome. Intriguingly, similar mismatches in evolutionary rates are observed for HIV-2, Hepatitis B, and Hepatitis C viruses [ 27 , 43 – 47 ], leading us to speculate that such mismatches are a general feature of rapidly evolving chronic viral infections in humans.…”

How does the humoral response to HIV-2 infection differ from HIV-1 and can this explain the distinct natural history of infection with these two human retroviruses?

“…The rates of evolution and positive selection were twice as high in the first child compared to the second child. At the age of 5 years, the CD4 percentage decreased to 25% in the second child and despite antiviral therapy viral load was not controlled and the child died of AIDS aged 9 years [89]. The authors concluded that the lack of nAb activity may have contributed to the poor outcome of the second child, but because of the rarity of vertically acquired HIV-2 infection, it is hard to generalize from these data.…”

“…In a study by Rocha et al the evolution of HIV-2 envelope under the selective pressure of nAbs was compared from the early stages of the HIV-2 infection in two patients with different clinical outcomes [89]. They followed HIV-2 evolution from acute to chronic stages of infection in two children infected by vertical transmission (a relatively rare event, estimated to occur at a frequency of 0-4%).…”

Engineering broadly neutralizing antibodies for HIV prevention and therapy

“…In this review, we focus on engineering bNAbs against HIV-1 infection but much can be learned from natural HIV-2 humoral immunity. At the level of the infected individual, HIV-2 Env evolves at equivalent/faster rates than HIV-1 [40, 41], likely due to selective pressure from NAb responses [42]. Antigenic differences allowing for the greater generation of NAb responses in HIV-2 as compared to HIV-1 include greater stability of the Env trimer [43], less glycan shielding and a more ‘open’ conformation allowing for greater accessibility of NAb epitopes [36, 44], and greater structural and functional constraints to diversity in some NAb epitopes as compared to HIV-1 [45].…”