Differences in the expression of histocompatibility antigen-DR and in anti-mycobacterial activity of monocytes from HIV-infected individuals.

This study assesses the changes in the expression of histocompatibility antigen (HLA)-DR by mononuclear phagocytes from HIV-infected individuals. Overnight culture of monocytes resulted in an increase in HLA-DR expression by monocytes from uninfected individuals. In contrast, the expression of HLA-DR by monocytes from HIV-infected patients decreased spontaneously and was most pronounced in patients with clinical AIDS. We also found that Mycobacterium avium grew within monocytes from patients infected with HIV. The correlation between major histocompatibility complex (MHC) class II expression and Mycobacterial growth which has been reported in mice was not observed in monocytes from HIV-infected patients.

Immune responses to hepatitis C and non-hepatitis C antigens in hepatitis C virus infected and HIV-1 coinfected patients.

OBJECTIVE: To characterize immune phenotype and function in hepatitis C virus (HCV) infection in the presence and absence of HIV-1 infection. DESIGN: Cross-sectional comparison among controls (group A), patients with HCV infection (group B), HCV-HIV-1 coinfected patients (group C), coinfected patients receiving treatment for HIV-1 (group D), and untreated HIV-1 infected patients (group E). METHODS: Flow cytometric analysis for lymphocyte phenotypes, lymphocyte proliferation and cytokine production by ELISPOT. RESULTS: HCV infected patients tended to have an increased percentage of activated (CD38, HLA-DR) CD8 cells (group A, 2+/-1.4%; group B, 6+/-3.9%; P=0.08). Proliferative responses to non-HCV antigens were comparable in group A and group B subjects. A greater proportion of group B patients had stimulation indices (SI) > 3 to the HCV protein NS3 compared to group C and D patients (67%, 0%, and 11% respectively; P < 0.003), but only two patients in group B had SI > or = 5. The SI to NS3 was significantly higher in group B patients [median, 4; interquartile range (IQR), 3-9) than in group C (median, 2; IQR, 1-3; P < 0.04) or group D (median, 1; IQR, 1-4; P < 0.009) patients. Plasma HCV RNA levels correlated directly with alanine aminotransferase levels (p, 0.52; P < 0.05) and inversely with the number of CD4 lymphocytes (rho, -0.55; P < 0.009) and proliferation to NS3 (p, -0.55; P < 0.009). CONCLUSIONS: Lymphocytes of HCV infected patients show weak proliferative responses to HCV antigens while responses to other antigens are preserved. Infection with HIV-1 potentiates this deficiency. Poor CD4 T cell responses to HCV are associated with and may determine the failure to control HCV propagation.

The nef gene from a long-term HIV type 1 nonprogressor.

We examined the nef gene of HIV-1 in a long-term nonprogressor to look for evidence suggesting an attenuated virus. The nef gene was previously shown to be required for induction of AIDS. Simian immunodeficiency virus (SIV) deleted in nef, while infectious, fails to sustain the high viral loads necessary for the induction of AIDS in infected adult rhesus monkeys. The human subject of this report was found to harbor virus (HIV-1 Sur25) encoding open-nef reading frames. However, the nef genes of this subject bore a signature point mutation: a cysteine at amino acid 138. The sequence at this position was identical in all clones examined over a 3-year period. When this sequence was compared to the sequence database for AIDS and human retroviruses at Los Alamos, New Mexico, several isolates from other asymptomatic individuals were also found to encode nef genes with a cysteine at position 138. Furthermore, Cys-138 was found in chimpanzee immunodeficiency virus (CIV), a lentivirus that is similar to HIV but does not cause AIDS in chimpanzees. Multiple cysteines are also found in the nef gene of African green monkey virus, SVIagm, including cysteine at the position analogous to Cys-138. While seroprevalence of SIVagm is high in the wild, there is no known disease associated with this virus. The pathogenic virus isolated from Asian macaques, SIVmac, encodes a Nef protein that has few cysteines. Although the virus HIVSur25 encodes a completely open-nef gene, the virus from this individual is similar to attenuated SIVmac (SIVmac239/nef-deletion) as well as HIV deleted in nef in its growth properties in H9 cells. Nef containing a cysteine at position 138 was shown to be responsible for determining the ability to grow in H9.

The nef Gene of SIVmac239 Is Necessary for Efficient Growth in H9 Cells.

AIDS viruses require an intact functional nef gene in order to induce disease. The nonpathogenic molecular cloned virus SIVmac239nef-deletion encodes a truncated nef gene. This attenuated reading frame is expressed both in vitro and in a virus-infected animal in vivo. Encoding the first 58 amino acids of Nef, the reading frame retained its ability to down-modulate CD4 from the surface of T cells. CD4-down-modulated stable cell lines expressing full-length and truncated nef genes were significantly less infected by SIV. SIVmac239nef-open and SIVmacnef-deletion encoding a truncated nef clearly differed in replication kinetics in H9 cells and H9-derived cell lines. SIVmac239nef-deletion replication was delayed in H9. Copyright 1996 S. Karger AG, Basel

The expression of HLA-DR by monocytes from black and from white donors: different requirements for protein synthesis.

Epidemiologic data indicates that blacks may be more susceptible than whites to infection by Mycobacterium tuberculosis. Resistance to the in vivo growth of Mycobacteria in mice correlates with the persistence of MHC class II expression by peritoneal macrophages. The expression of HLA-DR by human monocytes from different groups of individuals also differs. The increase in the expression of HLA-DR by monocytes that occurs upon in vitro culture was prevented by the protein synthesis inhibitor cycloheximide (CHX) in a majority of black donors. In contrast, the increase in HLA-DR expression by monocytes from the majority of white donors was unaffected.

Characterization of high-risk HIV-1 seronegative hemophiliacs.

Mechanisms that protect most high-risk HIV-1 seronegative (HRSN) persons are not well understood. Among hemophiliacs from the Multicenter Hemophilia Cohort Study who remained HIV-1 seronegative despite a high (94%) risk for acquisition of HIV-1 infection, only 7/43 were homozygous for the protective CCR5 Delta32 polymorphism. Among the remainder, neither CCR5 density nor beta-chemokine production, nor in vitro susceptibility to infection with the HIV-1 isolate JR-FL could distinguish HRSN hemophiliacs from healthy controls. When compared to lymphocytes of healthy controls not at risk for HIV-1 infection, diminished spontaneous lymphocyte proliferation was seen in lymphocytes of HRSN hemophiliacs as well as in lymphocytes of hemophiliacs not at risk for HIV-1 infection. Surprisingly sera/plasmas obtained from high-risk HIV-1 seropositve hemophiliacs prior to seroconversion more often contained alloreactive antibodies than date-matched sera/plasmas obtained from HRSN hemophiliacs. Thus alloreactivity may predispose to acquisition of HIV-1 infection after parenteral exposure.