T. I. de Silva

Potent Autologous and Heterologous Neutralizing Antibody Responses Occur in HIV-2 Infection across a Broad Range of Infection Outcomes

ABSTRACT Few studies have explored the role of neutralizing antibody (NAb) responses in controlling HIV-2 viremia and disease progression. Using a TZM-bl neutralization assay, we assessed heterologous and autologous NAb responses from a community cohort of HIV-2-infected individuals with a broad range of disease outcomes in rural Guinea-Bissau. All subjects (n = 40) displayed exceptionally high heterologous NAb titers (50% inhibitory plasma dilution or 50% inhibitory concentration [IC50], 1:7,000 to 1:1,000,000) against 5 novel primary HIV-2 envelopes and HIV-2 7312A, whereas ROD A and 3 primary envelopes were relatively resistant to neutralization. Most individuals also showed high autologous NAb against contemporaneous envelopes (78% of plasma-envelope combinations in 69 envelopes from 21 subjects), with IC50s above 1:10,000. No association between heterologous or autologous NAb titer and greater control of HIV-2 was found. A subset of envelopes was found to be more resistant to neutralization (by plasma and HIV-2 monoclonal antibodies). These envelopes were isolated from individuals with greater intrapatient sequence diversity and were associated with changes in potential N-linked glycosylation sites but not CD4 independence or CXCR4 use. Plasma collected from up to 15 years previously was able to potently neutralize recent autologous envelopes, suggesting a lack of escape from NAb and the persistence of neutralization-sensitive variants over time, despite significant NAb pressure. We conclude that despite the presence of broad and potent NAb responses in HIV-2-infected individuals, these are not the primary forces behind the dichotomous outcomes observed but reveal a limited capacity for adaptive selection and escape from host immunity in HIV-2 infection.

Correlates of T-cell–mediated viral control and phenotype of CD8+ T cells in HIV-2, a naturally contained human retroviral infection

While a significant proportion of HIV-2-infected individuals are asymptomatic and maintain undetectable viral loads (controllers), 15% to 20% progress to AIDS and are predicted by detectable viremia. Identifying immune correlates that distinguish these 2 groups should provide insights into how a potentially pathogenic retrovirus can be naturally controlled. We performed a detailed study of HIV-2-specific cellular responses in a unique community cohort in Guinea-Bissau followed for over 2 decades. T-cell responses were compared between controllers (n = 33) and viremic subjects (n = 27) using overlapping peptides, major histocompatibility complex class I tetramers, and multiparameter flow cytometry. HIV-2 viral control was significantly associated with a high-magnitude, polyfunctional Gag-specific CD8(+) T-cell response but not with greater perforin upregulation. This potentially protective HIV-2-specific response is surprisingly narrow. HIV-2 Gag-specific CD8(+) T cells are at an earlier stage of differentiation than cytomegalovirus-specific CD8(+) T-cells, do not contain high levels of cytolytic markers, and exhibit low levels of activation and proliferation, representing distinct properties from CD8(+) T cells associated with HIV-1 control. These data reveal the potential T-cell correlates of HIV-2 control and the detailed phenotype of virus-specific CD8(+) T cells in a naturally contained retroviral infection.

Full-length sequence of KIR3DL1*01501 allele found in Sub-Saharan Africa by long-range sequencing.

Full-length KIR3DL1*01501 differing from KIR3DL1*0150201 with 10 SNPs and 2 nucleotide deletion in intron 7.

A novel KIR3DL1*0200102 allele isolated from a West African donor by sequence-based typing

KIR3DL1*0200102 allele differs from KIR3DL1*0200101 with four single nucleotide polymorphisms in introns 5 and 6, respectively.

KIR3DL1*0250103: a novel three-domain KIR allele isolated in West African samples

The full length sequence of KIR3DL1*0250103 differs from that of KIR3DL1*0150101 with nine single-nucleotide polymorphisms.

Identification of a novel three-domain KIR allele: KIR3DL1*087 using high-resolution molecular techniques.

KIR3DL1*087 is significantly different from KIR3DL1*0010101 with multiple non-synonymous changes and insertion/deletion sites.

Full-length sequence of KIR3DL1*0310102 detected in DNA samples from West Africa.

KIR3DL1*0310102 differs from KIR3DL1*0150101 with 11 nucleotide substitutions.

KIR3DL1*0250102: a novel three‐domain KIR subtype identified in West Africa

KIR3DL1*0250102 differs from the common West African KIR3DL1*0150101 by 11 single nucleotide polymorphisms (SNPs).

KIR3DL1*0040102 – a novel three-domain KIR subtype isolated from donors of African descent.

KIR3DL1*0040102 allele differs from KIR3DL1*0040101 by a single-nucleotide change at position 12356 (intron 6).

A novel KIR3DL1*0150103 subtype identified in West Africa

A novel KIR3DL1*0150103 found in West Africa with five single nucleotide polymorphisms compared to KIR3DL1*0150101.