L.-M. Yindom

Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection

HIV-2 infection in the majority of infected subjects follows an attenuated disease course that distinguishes it from infection with HIV-1. Antigen-specific T cells are pivotal in the management of chronic viral infections but are not sufficient to control viral replication in HIV-1-positive subjects, and their function in HIV-2 infection is not fully established. In a community-based cohort of HIV-2 long-term nonprogressors in rural Guinea-Bissau, we performed what we believe is the first comprehensive analysis of HIV-2-specific immune responses. We demonstrate that Gag is the most immunogenic protein. The magnitude of the IFN-gamma immune response to the HIV-2 proteome was inversely correlated with HIV-2 viremia, and this relationship was specifically due to the targeting of Gag. Furthermore, patients with undetectable viremia had greater Gag-specific responses compared with patients with high viral replication. The most frequently recognized peptides clustered within a defined region of Gag, and responses to a single peptide in this region were associated with low viral burden. The consistent relationship between Gag-specific immune responses and viremia control suggests that T cell responses are vital in determining the superior outcome of HIV-2 infection. A better understanding of how HIV-2 infection is controlled may identify correlates of effective protective immunity essential for the design of HIV vaccines.

Highly avid, oligoclonal, early‐differentiated antigen‐specific CD8+ T cells in chronic HIV‐2 infection

HIV‐1‐specific CD8+ T cells are present in most HIV‐1‐infected people and play an important role in controlling viral replication, but the characteristics of an effective HIV‐specific T‐cell response are largely unknown. The majority of HIV‐2‐infected people behave as long‐term non‐progressors while those who progress to AIDS do so in a manner indistinguishable from HIV‐1. A detailed study of HIV‐2 infection may identify protective immune responses. Robust gag p26‐specific T‐cell responses are elicited during HIV‐2 infection and correlate with control of viremia. In this study, we analyzed features of an HLA‐B*3501‐restricted T‐cell response to HIV‐2 p26 that may contribute to virus control. In contrast to HIV‐1, HIV‐2‐specific T cells are at an early stage of differentiation (CD27+CD28+), a finding that relates directly to CD4+ T‐cell levels and inversely to immune activation. The cells demonstrate IFN‐γ secretion, oligoclonal T‐cell receptor Vβ gene segment usage, exceptional avidity and secretion of pro‐inflammatory cytokines. Despite the potentially strong selection pressure imposed on the virus by these cells, there was no evidence of HIV‐2 sequence evolution. We propose that in chronic HIV‐2 infection, the maintenance of early‐differentiated, highly avid CD8+ T cells could account for the non‐progressive course of disease. Such responses may be desirable from an HIV vaccine.

Killer-cell immunoglobulin-like receptors and malaria caused by Plasmodium falciparum in The Gambia.

The relevance of innate immune responses to Plasmodium falciparum infection, in particular the central role of natural killer (NK) cell-derived interferon gamma (IFN-γ), is becoming increasingly recognised. Recently, it has been shown that IFN-γ production in response to P. falciparum antigens is in part regulated by killer-cell immunoglobulin-like receptor (KIR) genes, and a study from malaria-exposed Melanesians suggested an association between KIR genotypes and susceptibility to infection. This prompted us to determine and compare the frequencies of 15 KIR genes in Gambian children presenting with either severe malaria (n = 133) or uncomplicated malaria (n = 188) and in cord-blood population control samples (n = 314) collected from the same area. While no significant differences were observed between severe and uncomplicated cases, proportions of individuals with KIR2DS2+C1 and KIR2DL2+C1 were significantly higher among malaria cases overall than in population control samples. In an exploratory analysis, activating KIR genes KIR2DS2, KIR3DS1 and KIR2DS5 were slightly higher in children in disease subgroups associated with the highest mortality. In addition, our data suggest that homozygosity for KIR genotype A might be associated with different malaria outcomes including protection from infection and higher blood parasitaemia levels in those that do get infected. These findings are consistent with a probable role of KIR genes in determining susceptibility to malaria, and further studies are warranted in different populations.

Association analysis between HLA-A, -B, -C, -DRB1, and -DQB1 with nasopharyngeal carcinoma among a Han population in Northwestern China.

BACKGROUND Most HLA association studies with NPC focus on Southern part of China. Thus, little is known about the genetic association of HLA with NPC in people from Northern China where the genetic background, environmental factors, and lifestyle are very different. METHODS 132 NPC patients and 168 normal controls of Han ethnic in Xinjiang Province were genotyped for HLA-A, -B, -C, -DRB1, and -DQB1 using the PCR-sequence specific primer technique. RESULTS Our results confirm previous findings that the HLA-B∗46 and HLA-A(∗)02B(∗)46 haplotypes are strongly associated with NPC, but we did not observe HLA-A(∗)11 and -B(∗)35 association with resistance to NPC. Instead, we found that HLA-B(∗)51 and -A(∗)30 are strongly associated with resistance to NPC. In addition, HLA-A(∗)24 was also strongly associated with susceptibility to NPC. CONCLUSION A unique pattern of HLA association with NPC susceptibility and resistance was found in patients from Xinjiang Province compared to the published data based on patients from Southern China and Taiwan. HLA-B(∗)46 is most significantly associated with NPC, and its frequency in endemic areas such as Guangdong Province, Taiwan, and Thailand is much higher than in Xinjiang Province and other areas with much less NPC occurrence. Interestingly, HLA-A(∗)30 is in contrast with the resistant allele, whose frequency is much lower in endemic areas but higher in Xinjiang and other areas with little NPC.

Identification of KIR3DL1*0050103 by the sequence‐based techniques

The new KIR3DL1*0050103 allele has a mutation at nucleotide position 6709 (C>T) in intron 5.

Identification of KIR3DL1*0150208 using long-range sequence-based techniques.

KIR3DL1*0150208 possesses five point mutations: 3037G>A, 4115A>G, 6053G>C, 8034A>G, and 9446T>C compared to KIR3DL1*0150201.

Report of a novel KIR3DS1*0130104 allele discovered using advanced molecular techniques

KIR3DS1*0130104 is identical to KIR3DS1*0130101 except for changes at positions 1768 (C>T) and 12617 (C>A).

Killer-cell immunoglobulin-like receptors and falciparum malaria in southwest Nigeria.

Killer-cell immunoglobulin-like receptors (KIRs) are a group of natural killer cell receptors (NKRs) that regulate NK-cell-mediated production of interferon gamma (IFN-γ) in response to infection. These receptors have recently been suggested to influence the severity of clinical Plasmodium falciparum malaria infection. We examined the KIR locus in relation to malaria in children from southwest Nigeria. Sequence specific priming (SSP)-PCR was used to detect the KIR genes. The presence or absence of fifteen different KIR genes was determined in each individual and the proportions compared across 3 clinical groups; asymptomatic malaria, uncomplicated clinical malaria and severe clinical malaria. The genes KIR2DL5, KIR2DS3 and KIR2DS5 were present in a significantly higher proportion of individuals in the asymptomatic control group than in the malaria cases. Furthermore, KIR2DS3 and KIR2DS5 were present in a higher proportion of uncomplicated malaria cases than severe malaria cases. Carriage c-AB2 genotype (which comprises all centromeric KIR genes including KIR2DL5, KIR2DS3 and KIR2DS5) decreases with severity of the disease suggesting that the KIR AB profile might be associated with protection from severe malaria infection in this population in Nigeria.

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.

Isolation of full-length HLA-C*18:02 allele in an individual from Sub-Saharan Africa.

The full‐length sequence of HLA‐C*18:02 differs from that of HLA‐C*18:01 by a single nucleotide polymorphism.