Improved virological response to highly active antiretroviral therapy in HIV‐1‐infected patients carrying the CCR5 Δ32 deletion

Abstract

BackgroundPatients heterozygous for the C-C chemokine receptor 5 (CCR5) D32 deletion spontaneously progress less rapidly to AIDS and death than do wild-type patients. We investigated whether the CCR5 D32 deletion has an impact on immunological, virological and clinical responses to highly active antiretroviral therapy (HAART) in HIV-1-infected patients. Patients and methodsWe included in the study 565 HIV-1-infected patients from the French HIV-1 infected cohort with documented date of serconversion (SEROCO)/haemophiliacs HIV-1 infected (HEMOCO) cohorts, who started HAART after 1996. We investigated virological responses to HAART at 6 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection or a 2 log HIV-1 RNA decrease) and at 12 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection) and clinical response to HAART by Kaplan-Meier survival curves, with AIDS and death as outcomes. ResultsThe D32 heterozygous patients (n 5 83; 15%) had a better virological response to HAART than wild-type patients (73 vs 53% at 6 months, P 5 0.01; and 60 vs 44% at 12 months, P 5 0.01). This better virological response was still observed after adjustment for antiretroviral status (whether or not patients were naïve to antiretroviral therapy), year of HAART initiation, number of new antiretroviral drugs and baseline viral load. There was no statistical difference between heterozygous patients and wild-type patients in terms of survival and AIDS-free survival. ConclusionsCCR5 D32 heterozygous patients were more likely to have a virological response to HAART than wild-type patients at 6 and 12 months. However, this virological response did not produce better immunological and clinical responses. The long-term impact of the D32 deletion on survival in HIV-1-infected treated patients should be investigated in a meta-analysis. Introduction C-C chemokine receptor 5 (CCR5), a receptor for the bchemokine RANTES, macrophage inflammatory protein (MIP)-1a and MIP-1b, is the most important chemokine receptor used by R5 HIV-1 strains for entry into CD4 cells.A 32-bp deletion (CCR5 D32) in the gene encoding the CCR5 coreceptor has been described [1][2][3]. Homozygous CCR5 D32/CCR5 D32 subjects are highly resistant to HIV-1 infection, although a few cases of infection have been reported [4][5][6]. Heterozygotes (CCR5 wt/CCR5 D32) are susceptible to HIV-1 infection, but progress more slowly to AIDS and death than wild-type patients (CCR5 wt/CCR5 wt) [7][8][9][10] 213 expression at the cell surface is diminished in D32 heterozygous patients and early plasma HIV-RNA viral load is lower in these patients than in wild-type patients [11]; this may explain why spontaneous HIV disease progression is slower in heterozygotes [9,10]. Since 1996, the use of highly active antiretroviral therapy (HAART) has provided substantial immunological (in terms of CD4 increase), virological (in terms of decrease in viral load) and clinical benefits to HIV-1-infected patients [12][13][14][15][16][17][18][19][20][21][...

Risk of All-Cause Mortality in HIV Infected Patients Is Associated with Clinical, Immunologic Predictors and the CCR5 Δ32 Deletion

“…An array of factors influencing survival were analyzed in this study including demographics as well as clinical and immunological parameters. The frequency of the CCR5 Δ32/wt heterozygotes in this study was 14.0% and is consistent to the previous reports for Caucasian populations, while use of archived samples allowed to avoid the bias related to the survival benefit of the mutation in HIV infected patients who may have died [8], [19], [20]. The near-significant difference between the male and female gender frequency might be related to the transmission route – higher number of women was infected sexually.…”

“…No significant effect of the Δ32 allele, survival and AIDS free survival was also found by Laurichesse et al [8]. Moreover, Brumme et al, did not find the association between the CCR5 Δ32/wt genotype and time to virological failure in the study of 436 individuals observed for the median follow-up of 22 months [22].…”

“…Lack of beneficial effect of the Δ32 allele among antiretroviral treated patients observed in our study might be associated not only to the size of the group, but also differences in the time from the infection to treatment initiation, which is related to late diagnosis of HIV and high prevalence of AIDS at the time of diagnosis. However, it must be noted that the Δ32 allele has been associated with the decrease in the likelihood of viral suppression failures, defined as HIV-RNA ≥200 copies/ml at 16–28 weeks of therapy, accelerated viral suppression to <200 HIV-RNA copies/ml, as well as significantly better virologic response to antiretrovirals both at 6 and 12 months following treatment initiation [8], [11], [36]. Moreover, a higher rate of the sustained virologic suppression during the observation period of up to 5 years of antiretroviral treatment in the CCR5 Δ32 / wt heterozygous patients was noted [9].…”

“…Studies of the long-term non-progression among HIV-infected patients have indicated higher frequency of this protective allele among individuals spontaneously controlling the infection [7]. This variant has also been associated with better virologic response to combined antiretroviral therapy (cART) as well as less frequent virologic failure, decreased risk of early death among perinatally infected children and protection from AIDS among antiretroviral-treated patients [8]–[11].…”

Better CD4+ T Cell Recovery in Brazilian HIV-Infected Individuals Under HAART Due to Cumulative Carriage of SDF-1-3A, CCR2-V64I, CCR5- D32 and CCR5-Promoter 59029A/G Polymorphisms

“…When the polymorphic alleles were analyzed individually, CCR5-D32 carriage was associated with improved CD4+ T cell gain during HAART, confirming previous studies showing a protective effect of CCR5-D32 on other markers of disease progression of the HIV-1 infection during HAART [13,21,25,29,[48][49][50]. The CCR5-D32 allele is known to encode a truncated protein that is not expressed on cell surface.…”