Mf McLane

HTLV-III IN SYMPTOM-FREE SERONEGATIVE PERSONS

Of 96 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and healthy individuals at risk for AIDS, 4 had no detectable antibodies to viral proteins, though human T-cell leukaemia (lymphotropic) virus type III was isolated from their lymphocytes. 3 of these subjects were symptom-free and 1 had lymphadenopathy. All 4 were sexual partners of patients with AIDS or AIDS-related complex. The occurrence of seronegative but virus-positive persons without clinical symptoms suggests that assays other than those detecting antibody to virus, perhaps based on detection of viral antigens or immune complexes, may be required to identify all infected individuals.

Association between Virus-Specific T-Cell Responses and Plasma Viral Load in Human Immunodeficiency Virus Type 1 Subtype C Infection

ABSTRACT Virus-specific T-cell immune responses are important in restraint of human immunodeficiency virus type 1 (HIV-1) replication and control of disease. Plasma viral load is a key determinant of disease progression and infectiousness in HIV infection. Although HIV-1 subtype C (HIV-1C) is the predominant virus in the AIDS epidemic worldwide, the relationship between HIV-1C-specific T-cell immune responses and plasma viral load has not been elucidated. In the present study we address (i) the association between the level of plasma viral load and virus-specific immune responses to different HIV-1C proteins and their subregions and (ii) the specifics of correlation between plasma viral load and T-cell responses within the major histocompatibility complex (MHC) class I HLA supertypes. Virus-specific immune responses in the natural course of HIV-1C infection were analyzed in the gamma interferon (IFN-γ)-enzyme-linked immunospot assay by using synthetic overlapping peptides corresponding to the HIV-1C consensus sequence. For Gag p24, a correlation was seen between better T-cell responses and lower plasma viral load. For Nef, an opposite trend was observed where a higher T-cell response was more likely to be associated with a higher viral load. At the level of the HLA supertypes, a lower viral load was associated with higher T-cell responses to Gag p24 within the HLA A2, A24, B27, and B58 supertypes, in contrast to the absence of such a correlation within the HLA B44 supertype. The present study demonstrated differential correlations (or trends to correlation) in various HIV-1C proteins, suggesting (i) an important role of the HIV-1C Gag p24-specific immune responses in control of viremia and (ii) more rapid viral escape from immune responses to Nef with no restraint of plasma viral load. Correlations between the level of IFN-γ-secreting T cells and viral load within the MHC class I HLA supertypes should be considered in HIV vaccine design and efficacy trials.

Identification of Human Immunodeficiency Virus Type 1 Subtype C Gag-, Tat-, Rev-, and Nef-Specific Elispot-Based Cytotoxic T-Lymphocyte Responses for AIDS Vaccine Design

ABSTRACT The most severe human immunodeficiency virus type 1 (HIV-1) epidemic is occurring in southern Africa. It is caused by HIV-1 subtype C (HIV-1C). In this study we present the identification and analysis of cumulative cytotoxic T-lymphocyte (CTL) responses in the southern African country of Botswana. CTLs were shown to be an important component of the immune response to control HIV-1 infection. The definition of optimal and dominant epitopes across the HIV-1C genome that are targeted by CTL is critical for vaccine design. The characteristics of the predominant virus that causes the HIV-1 epidemic in a certain geographic area and also the genetic background of the population, through the distribution of common HLA class I alleles, might impact dominant CTL responses in the vaccinee and in the general population. The enzyme-linked immunospot (Elispot) gamma interferon assay has recently been shown to be a reliable tool to map optimal CTL epitopes, correlating well with other methods, such as intracellular staining, tetramer staining, and the classical chromium release assay. Using Elispot with overlapping synthetic peptides across Gag, Tat, Rev, and Nef, we analyzed HIV-1C-specific CTL responses of HIV-1-infected blood donors. Profiles of cumulative Elispot-based CTL responses combined with diversity and sequence consensus data provide an additional characterization of immunodominant regions across the HIV-1C genome. Results of the study suggest that the construction of a poly-epitope subtype-specific HIV-1 vaccine that includes multiple copies of immunodominant CTL epitopes across the viral genome, derived from predominant HIV-1 viruses, might be a logical approach to the design of a vaccine against AIDS.

Antibodies to simian T-lymphotropic retrovirus type III in African green monkeys and recognition of STLV-III viral proteins by AIDS and related sera.

It has been theorized that the agent responsible for AIDS originated in Africa. An HTLV-I related virus found in African primates has in vitro characteristics and genetic structure similar to that of HTLV-I virus found in man and has been associated with lymphoma in 3 macaque species A retrovirus similar to HTLV-III has also been isolated from diseased macaques some of whom had immune system disease. To test the possibility that HTLV-III virus might have been transmitted to man via primates evidence was sought for an HTLV-related virus in primates from areas of Africa associated with AIDS in man. Sera were collected and studied from 3 central African primates--green monkeys chimpanzees and baboons. Human sera positive for HTLV-III were also collected from persons suffering from AIDS and AIDS Related Complex and from healthy homosexuals. Sera were prescreened for antibodies to STLV-III by membrane immunofluorescence. The 160 120 55 viral antigens of STLV- III were immunoprecipitated by both MIF-positive macaque sera and by HTLV-III positive sera from patients with AIDS and AIDS Related Complex. MIF-positive green monkey sera recognized STLV-III proteins but chimpanzee and baboon MIF-negative sera did not. 42% of healthy green monkeys had antibodies to STLV-III. None of the baboons and chimpanzees was seropositive. We suggest that STLV-III of African green monkeys may have been transmitted to man coincident with the recognition of AIDS in central Africa.

ANTIBODIES TO HUMAN T CELL LEUKAEMIA VIRUS-ASSOCIATED MEMBRANE ANTIGENS IN HAEMOPHILIACS: EVIDENCE FOR INFECTION BEFORE 1980

Human T cell leukaemia virus (HTLV), HTLV proviral DNA, and antibodies to HTLV or a related agent have recently been detected in patients with acquired immunodeficiency syndrome (AIDS). Antibodies against HTLV-related antigens were assayed by means of indirect living cell immunofluorescence of HTLV-infected cells in sera recently collected from Georgia haemophiliacs and in sera collected between 1976 and 1981 from New York haemophiliacs. 5 of 45 Georgia haemophiliacs and 8 of 48 New York haemophiliacs had antibodies to HTLV-associated cell membrane antigen (HTLV-MA). None of the control Georgia patients on haemodialysis or with chronic hepatitis had detectable antibodies. The 5 haemophiliac patients from Georgia with HTLV-MA had significantly fewer T4 lymphocytes than similar HTLV-MA-negative patients. There were no other significant immunological differences between these groups. These data suggest that transfusions with blood products may expose haemophiliacs to a substantial risk of acquiring HTLV or a related virus.