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CD4 & CD8 Resistance to HIV-Infection in IDUs
  "CD4 cell and CD8 cell-mediated resistance to HIV-1 infection in exposed uninfected intravascular drug users in Vietnam"
AIDS 2003; 17(10):1425-1434
Lien X. Truong a; Tram T. Luong a; Daniel Scott-Algara c; Pierre Versmisse d; Annie David d; Danielle Perez-Bercoff d; Ngai V. Nguyen b; Hung K. Tran a; Cuc T. Cao a; Arnaud Fontanet e; Jean-Yves Follezou f; Ioannis Theodorou g; Francoise Barre-Sinoussi d; Gianfranco Pancino d. aInstitut Pasteur and bHopital Binh-Trieu, Ho Chi Minh City, Vietnam; cUnite d'Immunohematologie et Immunopathologie, dUnite de Biologie des Retrovirus, and eUnite d'Epidemiologie des Maladies Emergentes, Institut Pasteur, Paris, France; fHopital Paul Brousse, Villejuif, France; and gLaboratoire d'Immunologie Cellulaire et Tissulaire, U543, Hopital Pitie-Salpetriere, Paris, France.
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. Peripheral blood mononuclear cells PBMC) or CD4 cell susceptibilities to HIV infection were evaluated using three HIV-1 isolates with different tropisms. Polymerase chain reaction analysis of HIV-1-DNA replication intermediates was used to characterize the restriction of HIV-1 replication in CD4 cells. Homologous CD8 cells were mixed with infected CD4 cells to evaluate their role in virus suppression.
Results: We observed a relative resistance to PBMC infection with HIV-1 in 21 out of 45 exposed uninfected IDU, but only in five out of 50 unexposed controls (P < 0.001). PBMC resistance was related either to an inhibition of HIV-1 replication in CD4 cells or to CD8 cell-mediated viral suppression. HIV-1 replication in CD4 cells was restricted at the early stages of the viral cycle.
Conclusion: Reduced PBMC susceptibility to HIV-1 infection was associated with resistance to infection in exposed uninfected IDU. Distinct mechanisms are involved in in-vitro resistance and may contribute to the apparent protection from HIV-1 transmission in this systemically exposed population.
Individuals who remain HIV-1 seronegative in spite of high-risk behaviours may be naturally protected from infection. Some of the mechanisms evoked to explain the resistance to the sexual transmission of HIV-1, such as low viral load or defective virus in infected partners or mucosal immune responses are less likely to be responsible for the occurrence of exposed uninfected individuals among IDU. Indeed, IDU are exposed to multiple HIV-1 strains as a result of the practice of needle sharing, and HIV transmission can occur by a systemic route. In this study we found that highly exposed yet apparently uninfected Vietnamese IDU exhibit a reduced susceptibility of PBMC to HIV-1 infection compared with unexposed controls.
We observed three main patterns corresponding to the specific cell subset involved in PBMC resistance: (i) a restriction of HIV-1 infection in CD4 cells; (ii) a CD8 cell suppression of HIV-1 replication in otherwise permissive CD4 cells; or (iii) a combination of reduced viral replication in CD4 cells and of an HIV-1-suppressive activity by CD8 cells.
The restriction of viral replication in CD4 cells mainly affected the R5 HIV-1 BaL. Such a resistance may be relevant in natural infection, because R5 viruses are preferentially involved in HIV-1 transmission. The mutations of the CCR5 gene that have been associated with HIV-1 resistance in Caucasian populations were absent in Vietnamese IDU. Susceptibility to R5 HIV-1 infection has been related to the surface expression of CCR5, even in individuals carrying the wild-type CCR5. In our study the proportion of CD4 cells that expressed CCR5 was actually higher in exposed uninfected IDU than in controls. The resistance to R5 viruses in exposed uninfected IDU thus does not appear to be linked to a reduced expression of CCR5. However, we cannot exclude variations of CCR5 expression during in-vitro cell culture. The proportion of CXCR4 CD4 cells was lower in exposed uninfected IDU than in controls, consistent with a lower proportion of naive T CD4 cells in exposed uninfected IDU compared with controls (data not shown). Whether this difference may influence cell susceptibility to X4 HIV-1 remains to be defined.
PCR analyses of viral retrotranscription in the three cases that presented the most pronounced CD4 cell resistance suggested that HIV-1 replication is restricted at early stages of the viral life cycle. Cell factors interfering with viral entry or with the subsequent process of uncoating and the generation of viral reverse transcription complex may be involved. Post-entry blocks of R5 HIV-1 in human CD4 T-cell clones or of SIVmac in CD4 cells from a monkey that resisted infection have been described. Evidence for the expression in monkey cells of one or more cellular inhibitory factors that prevent reverse transcription of HIV-1 was recently reported. It is conceivable that restriction systems with similar inhibitory activity may be present in a minor population of humans.
In our study, CD8 cell inhibition of HIV-1 infection was also associated with the control of HIV-1 replication. CD8 cells may control HIV-1 infection by secreting inhibitory molecules or by cytotoxic mechanisms. An increase in [beta]-chemokine secretion was associated with protection in exposed uninfected individuals in some studies but not in others. In our study, [beta]-chemokine secretion by activated PBMC was not increased in the exposed uninfected IDU group compared with controls, and thus does not seem to account for the differences in resistance to HIV-1. Moreover, in several cases, CD8 cells were able to inhibit not only R5 viruses but also a X4 virus, suggesting cell antiviral factor or cell antiviral factor-like suppressive activities. Interestingly, the levels of viral replication in CD8/CD4 co-cultures corresponded to or were lower than the levels found in PBMC, suggesting that HIV-1 replication in PBMC is mainly the result of an interaction between its replicative capacity in target CD4 cells and the suppressive activity of CD8 cells. Further studies are required to identify the underlying mechanisms.
Reduced PBMC susceptibilities to HIV-1 infection have been described in seronegative partners of HIV-infected individuals whereas significant differences in cell susceptibilities to HIV-1 between persistently seronegative sex workers and controls were not found. Multiple mechanisms are probably involved in the resistance to HIV-1 infection, and immune-mediated responses were detected in exposed uninfected IDU. Our results support the possibility that a relative cell resistance to HIV-1 infection, either as a result of CD4 cell resistance or CD8 cell-mediated inhibition, contribute to the protection from HIV-1 infection.
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