Risk of HIV Infection and Lethality Are Decreased in CCR5del32 Heterozygotes: Focus Nosocomial Infection Study and Meta-analysis

Abstract

CCR5del32 Homozygous deletion in the chemokine receptor R5 gene provides almost complete protection to individuals against HIV infection. However, data relating to the protective effect forCCR5del32 heterozygous individuals have been contradictory. The frequency of theCCR5del32allele in population control cohorts was compared with that of a group of children (27 Kalmyks and 50 Russians) infected by G-subtype HIV-1 in a nosocomial outbreak. The frequency of theCCR5del32allele was shown to be lower among the infected children in comparison with that of the control group; however, the difference was small and statistically insignificant. Similar results were obtained in a number of earlier studies. The insignificance of the small differences could be a result of one of two reasons. (i) The fact that there is no protective effect of the heterozygous state, and that the phenomenon depends only on the fluctuation of allele frequencies. In this case, there would be no differences even if the infected cohort is enlarged. (ii)The protective effect of the heterozygous state is real; however, the size of the studied cohort is insufficient to demonstrate it. In order to discern between these two reasons, a meta-analysis of data from 25 published articles (a total of 5,963 HIV-infected individuals and 5,048 individuals in the control group, including the authors’ own data) was undertaken. A conclusion was drawn from the meta-analysis that theCCR5del32 allele protects individuals against the HIV infection even in a heterozygous state (OR=1.22, 95%CI=1.10–1.36). The risk of HIV infection forCCR5 wt/del32 heterozygotes was lower by at least 13% as compared to that for wild typeCCR5 wt/wthomozygotes. Prior to this study, no data of the type or any conclusions had been published for Caucasians. The mortality rate in the 15 years following the infection was found to be approximately 40% lower forCCR5del32 heterozygotes in comparison with that for the wild type homozygotes in the studied group. The size of the studied group was insufficient to claim difference validity (OR=2.0;p= 0.705), even though the effect quantitatively matched the published data. The features of the meta-analysis influencing the threshold level and the statistical validity of the effects are being discussed. The level of theCCR5del32 protective effect on the chances to be infected with HIV and on the outcome of the HIV infection was assessed for various ethnic groups.

The number of CCR5 expressing CD4+ T lymphocytes is lower in HIV-infected long-term non-progressors with viral control compared to normal progressors: a cross-sectional study

“…These molecules act at several key steps of the HIV lifecycle and can avert viral infection or replication in a cell-specific way. As they control HIV infection, it is possible that genetic alterations or levels of expression are related to differences in HIV progression [ 39 ].…”

Association of Diverse Genotypes and Phenotypes of Immune Cells and Immunoglobulins With the Course of HIV-1 Infection

“…For instance, one study showed that reduced cell surface CCR5 in CCR5 WT/Δ32 heterozygotes yielded limited protection, whereas Δ32 homozygotes were almost completely resistant to HIV infection ( 72 ). Meta-analysis of 5,963 HIV-infected individuals and 5,048 controls confirmed that among Caucasians, the risk of HIV infection is at least 13% lower in CCR5 WT/Δ32 heterozygotes than in CCR5 WT/WT homozygotes ( 73 ). Additional evidence for the protective role of the CCR5Δ32 allele is provided by the population of Vlach Gypsies in Hungary, in which the frequency of CCR5Δ32 is elevated and the incidence of HIV/AIDS is lower ( 74 ).…”

Поліморфізм Генів При Віл-Інфекції

“…Індивіди, гомозиготні за CCR5del32, частка яких в європейських популяціях становить 1-2 %, володіють високою, але не абсолютною стійкістю до інфікування. Серед ВІЛ-інфікованих гомозиготні носії CCR5del32 реєструються дуже рідко -описано всього 12 таких випадків із понад 20 000 обстежених, і у більшості з них вірус володіє тропізмом до рецептора CXCR4, але не до CCR5 [31]. Захисний ефект у гомозиготних носіїв за алелем CCR5del32 підтверджений як у ряді епідеміологічних досліджень (збільшення частоти гомозигот серед ВІЛ-негативних індивідуумів сприяло ризику інфікування), так і при інфікуванні in vitro клітин CD4 + , отриманих від індивідів з різними генотипами.…”

“…Таким чином, на популяційному рівні захист від інфікування ВІЛ та зниження смертності ВІЛ-інфікованих навіть у групах з високою частотою CCR5del32 (15 %) невелика. Крім ССR5del32 є інші гени, які впливають на сприйнятливість до ВІЛ-інфекції [31].…”