Optimal Maturation of the SIV-Specific CD8 T Cell Response after Primary Infection Is Associated with Natural Control of SIV: ANRS SIC Study.

Highly efficient CD8 T cells are associated with natural HIV control, but it has remained unclear how these cells are generated and maintained. We have used a macaque model of spontaneous SIVmac251 control to monitor the development of efficient CD8 T cell responses. Our results show that SIV-specific CD8 T cells emerge during primary infection in all animals.

HIV Controllers Have Low Inflammation Associated with a Strong HIV-Specific Immune Response in Blood.

HIV controllers (HIC) maintain control of HIV replication without combined antiretroviral treatment (cART). The mechanisms leading to virus control are not fully known. We used gene expression and cellular analyses to compare HIC and HIV-1-infected individuals under cART.

Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8+ T Cells in HIV-2-Infected Controllers.

Compared with HIV-1, HIV-2 infection is characterized by a larger proportion of slow or nonprogressors. A better understanding of HIV-2 pathogenesis should open new therapeutic avenues to establish control of HIV-1 replication in infected patients. In this study, we studied the production of CD8(+) T cells and their capacity for viral control in HIV-2 controllers from the French ANRS CO5 HIV-2 cohort.

Dendritic Cells from HIV Controllers Have Low Susceptibility to HIV-1 Infection In Vitro but High Capacity to Capture HIV-1 Particles.

HIV controllers (HICs), rare HIV-1 infected individuals able to control viral replication without antiretroviral therapy, are characterized by an efficient polyfunctional and cytolytic HIV-specific CD8+ T cell response. The mechanisms underlying the induction and maintenance of such response in many HICs despite controlled viremia are not clear. Dendritic cells play a crucial role in the generation and reactivation of T cell responses but scarce information is available on those cells in HICs.

Long-term control of simian immunodeficiency virus (SIV) in cynomolgus macaques not associated with efficient SIV-specific CD8+ T-cell responses.

Unlabelled: The spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8(+) T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8(+) T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8(+) T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8(+) T-cell responses.

Potential role for HIV-specific CD38-/HLA-DR+ CD8+ T cells in viral suppression and cytotoxicity in HIV controllers.

Background: HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38-/HLA-DR+ HIV-specific CD8+ T cells. Here we examined the role of this subset in HIC status.

Both HLA-B*57 and plasma HIV RNA levels contribute to the HIV-specific CD8+ T cell response in HIV controllers.

CD8(+) T cell responses are thought to play an important role during HIV infection, particularly in HIV controllers (HIC) in whom viral replication is spontaneously controlled without any treatment. We have demonstrated that CD8(+) T cells from these subjects are able to suppress viral replication in vitro. In parallel, HIV-specific CD8(+) responses were shown to be strong and of high quality, with proliferative abilities and cytotoxic capacities, in HIC.

CD8 T-cells from most HIV-infected patients lack ex vivo HIV-suppressive capacity during acute and early infection.

The strong CD8+ T-cell-mediated HIV-1-suppressive capacity found in a minority of HIV-infected patients in chronic infection is associated with spontaneous control of viremia. However, it is still unclear whether such capacities were also present earlier in the CD8+ T cells from non controller patients and then lost as a consequence of uncontrolled viral replication. We studied 50 patients with primary HIV-1-infection to determine whether strong CD8+ T-cell-mediated HIV suppression is more often observed at that time.

Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.

Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection.

Restriction of HIV-1 replication in macrophages and CD4+ T cells from HIV controllers.

How HIV controllers (HICs) maintain undetectable viremia without therapy is unknown. The strong CD8(+) T-cell HIV suppressive capacity found in many, but not all, HICs may contribute to long-lasting viral control. However, other earlier defense mechanisms may be involved.

Ex vivo T cell-based HIV suppression assay to evaluate HIV-specific CD8+ T-cell responses.

To advance T cell-based HIV vaccine development, it is necessary to evaluate the immune correlates of a protective CD8(+) T-cell response. We have developed an assay that assesses the capacity ex vivo of HIV-specific CD8(+) T cells to suppress HIV-1 infection of autologous CD4(+) T cells. This assay directly reflects the ultimate effector function of CD8(+) T cells, the elimination of infected cells, and accurately differentiates the effective CD8(+) T-cell response in spontaneous HIV controllers from ineffective responses in other patients.

Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses.

"HIV controllers" (HICs) are rare individuals in whom HIV-1 plasma viral load remains undetectable without antiretroviral treatment. This spontaneous viral control in HICs is usually associated to strong functional HIV-specific CD8(+) T cell responses. Accordingly, we have recently shown that CD8(+) T cells from HICs strongly suppress ex vivo HIV-1 infection of autologous CD4(+) T cells, suggesting a crucial role of this response in vivo.

Biological and physical characterization of the X4 HIV-1 suppressive factor secreted by LPS-stimulated human macrophages.

LPS-stimulated macrophages release soluble factors that inhibit HIV-1 infection in both CD4(+) T lymphocytes and macrophages. These inhibitory factors include the CCR5 ligands RANTES, MIP-1alpha and MIP-1beta, which selectively block R5 HIV-1 strains, and a still unidentified factor with activity against X4 HIV-1 strains that we designate soluble macrophage-derived anti-HIV factor (MDAF). Here, we used X4 HIV-1 strains as specific probes to investigate the biological and physical characteristics of MDAF without the confounding effect of CCR5-binding chemokines.

HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype.

Some rare HIV-1-infected individuals, referred to as HIV controllers (HIC), have persistently undetectable plasma viral load in the absence of therapy. This control of HIV-1 replication has been associated with a strong, multifunctional specific CD8(+) T cell response. However, no direct link between this immune response and the control of viremia has so far been provided.

Persistent resistance to HIV-1 infection in CD4 T cells from exposed uninfected Vietnamese individuals is mediated by entry and post-entry blocks.

Background: We have previously reported that CD4 T cells from some exposed uninfected (EU) Vietnamese intravenous drug users are relatively resistant to HIV infection in vitro. Here, we further characterized the restriction of viral replication in CD4 T cells from five EUs and assessed its persistence in serial samples.

Results: CD4 T cells and/or PBMC sampled during a period of between 2 and 6 years were challenged with replication-competent HIV-1 and other retroviral particles pseudotyped with envelope proteins of various tropisms.

The engagement of activating FcgammaRs inhibits primate lentivirus replication in human macrophages.

We previously reported that the stimulation of monocyte-derived macrophages (MDM) by plate-bound i.v. Igs inhibits HIV-1 replication.

Reduced CD4 T cell activation and in vitro susceptibility to HIV-1 infection in exposed uninfected Central Africans.

Background: Environmentally driven immune activation was suggested to contribute to high rates of HIV-1 infection in Africa. We report here a study of immune activation markers and susceptibility to HIV-1 infection in vitro of forty-five highly exposed uninfected partners (EUs) of HIV-1 infected individuals in Central African Republic, in comparison with forty-four low-risk blood donors (UCs).

Results: Analysis of T lymphocyte subsets and activation markers in whole blood showed that the absolute values and the percentage of HLA-DR+CD4 T cells and of CCR5+CD4 T cells were lower in the EUs than in the UCs (p = 0.

New CCR5 variants associated with reduced HIV coreceptor function in southeast Asia.

Background: Despite multiple exposure to HIV-1, some individuals remain uninfected. This resistance has been associated with homozygosity for a 32 base pair deletion in the gene for the CCR5 receptor. This variant occurs frequently in Caucasians but is extremely rare in Asians or Africans.

Cutting edge: increased NK cell activity in HIV-1-exposed but uninfected Vietnamese intravascular drug users.

We addressed the role of innate immunity in the protection against HIV-1 infection by studying NK cell function in 37 Vietnamese intravascular drug users (IDUs), who appeared to remain HIV-1 uninfected despite many years of high-risk exposure (exposed uninfected, EU), 10 IDUs who underwent seroconversion and 28 unexposed blood donors. Main results were: NK cell lytic activities against both the NK-susceptible K562 cell line and the NK-resistant Daudi cell line were significantly augmented in EU IDUs compared with either controls or seroconverters before or after seroconversion; NK cells producing the cytokines IFN-gamma and TNF-alpha and the beta chemokines CCL3, CCL4, and CCL5 were also increased in the EU IDUs, either after in vitro activation or without stimulation. The finding of an enhanced NK cell function in EU IDUs, especially compared with IDUs who became HIV-1 infected, supports the hypothesis that NK cells contribute to the protection against HIV-1 infection.

Broad spectrum of coreceptor usage and rapid disease progression in HIV-1-infected individuals from Central African Republic.

To study the progression of HIV-1 infection and coreceptor usages in Central African Republic, clinical data, plasma viral load, and coreceptor usage of sequential HIV-1 isolates were analyzed in a seroincident prospective cohort (PRIMOCA). Twenty-three HIV-1 infected individuals from the Central African Armed Forces were followed from 1995 to 2000. Viruses were isolated from 17 patients at various time points after seroconversion and their coreceptor usage was examined using GHOST cells expressing CD4 and one of the HIV-1 chemokine coreceptors CCR5, CXCR4, BOB/GPR15, and Bonzo/STRL33/CXCR6.

CD4 cell and CD8 cell-mediated resistance to HIV-1 infection in exposed uninfected intravascular drug users in Vietnam.

Objective: To identify mechanisms of resistance to HIV-1 infection in exposed uninfected individuals.

Design: We examined in-vitro cell susceptibility to HIV-1 infection in highly exposed Vietnamese intravascular drug users (IDU) who, despite a history of more than 10 years of drug use and a high prevalence of other blood-borne viral infections, remain apparently HIV uninfected.

Methods: Forty-five exposed uninfected IDU and 50 blood donors were included in the study.

Positive regulation of CXCR4 expression and signaling by interleukin-7 in CD4+ mature thymocytes correlates with their capacity to favor human immunodeficiency X4 virus replication.

The emergence of X4 human immunodeficiency virus type 1 (HIV-1) variants in infected individuals is associated with poor prognosis. One of the possible causes of this emergence might be the selection of X4 variants in some specific tissue compartment. We demonstrate that the thymic microenvironment favors the replication of X4 variants by positively modulating the expression and signaling of CXCR4 in mature CD4(+) CD8(-) CD3(+) thymocytes.

SIVcpz from a naturally infected Cameroonian chimpanzee: biological and genetic comparison with HIV-1 N.

Thus far, simian immunodeficiency virus from chimpanzees (SIVcpz) genomes have been characterized as Pan troglodytes troglodytes and show a strong relation with human immunodeficiency virus (HIV)-1 N in their env genes. We fully characterized another SIVcpz from P. t.

env sequences of simian immunodeficiency viruses from chimpanzees in Cameroon are strongly related to those of human immunodeficiency virus group N from the same geographic area.

Human immunodeficiency virus type 1 (HIV-1) group N from Cameroon is phylogenetically close, in env, to the simian immunodeficiency virus (SIV) cpz-gab from Gabon and SIVcpz-US of unknown geographic origin. We screened 29 wild-born Cameroonian chimpanzees and found that three (Cam3, Cam4, and Cam5) were positive for HIV-1 by Western blotting. Mitochondrial DNA sequence analysis demonstrated that Cam3 and Cam5 belonged to Pan troglodytes troglodytes and that Cam4 belonged to P.

Predominance of CCR5-dependent HIV-1 subtype E isolates in Cambodia.

To investigate the genetic and biologic features of HIV-1 strains circulating in Cambodia, viruses from 95 HIV-1-seropositive individuals were subtyped by heteroduplex mobility assay (HMA) and 23 were further analyzed for their biologic characteristics. Eighty-nine individuals were clearly infected by HIV-1 subtype E. The other six samples were sequenced, together with 17 HMA subtype E samples.