Abstract
Genetic and immunologic analyses of epidemiologically-linked HIV transmission enable insights into the impact of immune responses on clinical outcomes. Human vaccine trials and animal studies of HIV-1 infection have suggested immune correlates of protection; however, their role in natural infection in terms of protection from disease progression is mostly unknown. Four HIV-1+ Cameroonian individuals, three of them epidemiologically-linked in a polygamous heterosexual relationship and one incidence-matched case, were studied over 15 years for heterologous and cross-neutralizing antibody responses, antibody binding, IgA/IgG levels, antibody-dependent cellular cytotoxicity (ADCC) against cells expressing wild-type or CD4-bound Env, viral evolution, Env epitopes, and host factors including HLA-I alleles. Despite viral infection with related strains, the members of the transmission cluster experienced contrasting clinical outcomes including cases of rapid progression and long-term non-progression in the absence of strongly protective HLA-I or CCR5Δ32 alleles. Slower progression and higher CD4/CD8 ratios were associated with enhanced IgG antibody binding to native Env and stronger V1V2 antibody binding responses in the presence of viruses with residue K169 in V2. ADCC against cells expressing Env in the CD4-bound conformation in combination with low Env-specific IgA/IgG ratios correlated with better clinical outcome. This data set highlights for the first time that V1V2-directed antibody responses and ADCC against cells expressing open, CD4-exposed Env, in the presence of low plasma IgA/IgG ratios, can correlate with clinical outcome in natural infection. These parameters are comparable to the major correlates of protection, identified post-hoc in the RV144 vaccine trial; thus, they may also modulate the rate of clinical progression once infected. The findings illustrate the potential of immune correlate analysis in natural infection to guide vaccine development.
Highlights
In the quest for an effective HIV-1 vaccine, a definitive understanding of which immune responses should be induced to protect or control HIV infection remains elusive
Four Cameroonian HIV+ individuals, one male (#m) and three females (#f1, #f2, and #f3), were studied longitudinally from 2002 to 2017 (Figures 1, 2). #m and #f1 experienced a progressive course of the disease, whereas #f2 and #f3 were a long-term non-progressor (LTNP) and a slow progressor, respectively
Epidemiologic linkages among participants #m, #f1, and #f2 were confirmed through their genetically related unique recombinant form (URF) viruses, which comprised a monophyletic clade with high statistical support in env phylogenetic trees (Figures 2B, 3A; Supplementary Figures 1, 2, and Supplementary Table 1)
Summary
In the quest for an effective HIV-1 vaccine, a definitive understanding of which immune responses should be induced to protect or control HIV infection remains elusive. The only vaccine study that showed modest protection from HIV-1 infection of 31.2% after 3.5 years (modified intention-to-treat analysis), RV144, suggested that non-neutralizing Abs (nnAbs) directed against the V1V2 envelope region inversely correlated with infection risk [4,5,6]. As suggested after RV144, have been replicated partly in non-human primates [9, 10]; subtle differences exist between humans and monkeys with regards to immune responses and antibody repertoires, such as the structure and functionality of IgG3 and IgA subclasses [11, 12]. A better understanding of protective immune responses in natural infection and how this knowledge can be used to direct vaccine research is needed
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