C-C chemokines, pivotal in protection against HIV type 1 infection

Abstract

Exposure to HIV type 1 (HIV-1) does not usually lead to infection. Although this could be because of insufficient virus titer, there is now abundant evidence that some individuals resist infection even when directly exposed to a high titer of HIV. This protection recently has been correlated with homozygous mutations of an HIV-1 coreceptor, namely CCR5, the receptor for the ␤-chemokines. Moreover, earlier results already had shown that the same chemokines markedly suppress the nonsyncitial inducing variants of HIV-1, the chief virus type transmitted from person to person. CCR5 mutation, as a unique mechanism of protection, is, however, suspect because HIV-1 variants can use other chemokine receptors as their coreceptor. Moreover, recent results have established that infection can indeed sometimes occur with such mutations. Here, we report on transient natural resistance over time of most of 128 hemophiliacs who were inoculated repeatedly with HIV-1-contaminated Factor VIII concentrate from plasma during 1980-1985 before the development of the HIV blood test. Furthermore, and remarkably, 14 subjects remain uninfected to this date, and in these subjects we found homozygous CCR5 mutations in none but in most of them overproduction of ␤ chemokines. In vitro experiments confirmed the potent anti-HIV suppressive effect of these chemokines.

CCR5 promoter polymorphism determines macrophage CCR5 density and magnitude of HIV-1 propagation in vitro

“…Because β-chemokines may block HIV propagation in vitro [29,30] and heightened β-chemokine expression also has been seen in high-risk HIV-seronegative persons [31,32], we wanted to assess the relationship between β-chemokine production and genetic regulation of CCR5 expression. For these studies, we assayed cell culture supernatants for MIP-1α, MIP-1β, and RANTES by ELISA (R&D Systems, Minneapolis, MN, USA) after 48 h of cultivation without stimulation or after stimulation with PHA and IL-2 at suboptimal, nearoptimal, and optimal stimulation conditions.…”

Induction of G 1 cycle arrest in T lymphocytes results in increased extracellular levels of β-chemokines: A strategy to inhibit R5 HIV-1

“…Several studies have demonstrated that increased production of RANTES, MIP-1␣, and MIP-1␤ correlates with resistance to infection or a more favorable clinical prognosis, likely because of competition of the chemokines with HIV-1 for binding to CCR5 (2)(3)(4)(5)(6).…”

CCR5 genotype and plasma ß-chemokine concentration of Brazilian HIV-infected individuals

“…Several reports have suggested an association between exposed uninfected individuals and high levels of endogenous CC chemokines (macrophage inflammatory protein 1a and 1ß, MIP-1a and MIP-1ß) and RANTES (regulated-upon-activation, normal T expressed and secreted), suggesting that a chemokine may contribute to clinical resistance in some cases (4,5). Because the ß-chemokines are major components of the HIV-1 suppressive soluble factor extensively studied nowadays (6)(7)(8)(9)(10)(11)(12), the present study was undertaken to determine the relationship between plasma concentrations of MIP1a and RANTES and viral load in Brazilian HIV-1-infected subjects.…”

“…The reason for this difference is not known, although it may be due to variations among the individuals studied. One possible explanation for the lower MIP-1a plasma concentrations could be that the HIV-1 Tat protein may cause downregulation of mRNA and suppress the secretion of MIP-1a and MIP-1ß (5,18). In a recent study, MIP-1a was shown to have a 10-fold higher affinity than RANTES for CCR5 (19).…”