Proviral load and immune function in blood and lymph node during HIV-1 and HIV-2 infection.

Proviral load as well as lymphocyte phenotype and function were compared in peripheral blood and lymph node compartments of 17 HIV-1, 12 HIV-2 and three dually infected patients with lymphadenopathy. The mean percentage (95% confidence interval (CI)) of CD4+ cells was higher in lymph node mononuclear cells (LNMC) than in peripheral blood mononuclear cells (PBMC) in both infections, being 26.7% (21. 1%, 32.3%) and 15.3% (10.4%, 20.2%), respectively, for HIV-1-infected patients (P = 0.0001) and 32.3% (22.7%, 41.9%) and 22. 1% (13.6%, 30.6%), respectively, for HIV-2-infected patients (P = 0. 02). In both types of infection, proviral load adjusted for number of CD4+ cells was higher in LNMC than in PBMC: the geometric mean (95% CI) was 8937 (4991; 16 003) and 4384 (2260; 8503), respectively, for HIV-1 patients (P = 0.02) and 1624 (382; 6898) and 551 (147; 2058) DNA copies, respectively, for HIV-2 patients (P = 0.05). Proviral load in both compartments was closely correlated (HIV-1, r = 0.60, P = 0.01; and HIV-2, r = 0.83, P = 0.0003). In both infections, proliferation and interferon-gamma (IFN-gamma) production in response to purified protein derivative (PPD) was lower in LNMC than in PBMC, both of which, in turn, were lower than in healthy controls. These results indicate that in HIV-2 as in HIV-1 infection, infected cells have a tropism for the lymph nodes resulting in higher viral load in this compartment and lower lymphocyte responses to the recall antigen PPD which may increase susceptibility to tuberculosis.

A community-based study of human immunodeficiency virus type 2 provirus load in rural village in West Africa.

A community-based study of provirus load in human immunodeficiency virus (HIV) type 2-infected subjects was done in a rural village in Guinea-Bissau. HIV-2 provirus load varied considerably, with a geometric mean of 124.3 (95% confidence interval, 86.0-179.6) copies/10(5) CD4 cells, which is a level similar to that found in HIV-1 infection. Neither malaria parasitemia, active syphilis, or human T cell leukemia virus coinfection significantly influenced provirus load, nor did age. Eleven of 104 HIV-2-infected subjects had died after 3 years of follow-up; 9 of those who died had a high provirus load of > or = 100 copies/10(5) CD4 cells and a relatively low CD4 cell percentage of < 29%.

HIV type 2 proviral load measured by quantitative polymerase chain reaction correlates with CD4+ lymphopenia in HIV type 2-infected individuals.

The efficiency of detection of 2 sets of primer pairs from putatively conserved regions of the human immunodeficiency virus type 2 (HIV-2) genome were assessed in 86 seropositive individuals from The Gambia by nested polymerase chain reaction (PCR). HIV-2 long terminal repeat (LTR) target sequences were detected in DNA extracted from peripheral blood mononuclear cells (PBMCs) in 84 of 86 (97%) individuals whereas HIV-2 integrase (pol) gene sequences were detected in 39 of 41 (95%) individuals. The use of LTR target sequences and recombinant Pfu DNA polymerase, rather than Taq polymerase, in a modified secondary amplification reaction mediated the incorporation of 35S-labeled nucleotides in a quantitative radiometric assay. This sensitive assay was used to quantify HIV-2 proviral DNA in clinical samples and compared well with estimations by limiting end-point dilution of target molecules. A linear response between counts and the number of copies amplified from serial dilutions of pROD10 plasmid DNA (3-2000 copies) yielded a standard curve to allow extrapolation to clinical data. Increased levels of HIV-2 proviral DNA, expressed as copies per 10(5) CD4-positive lymphocytes, were associated with declining CD4 count in 63 adult patients (Spearman rank correlation, r = -0.71, n = 63, p < 0.001) and with the occurrence of HIV-related clinical disease. Kruskall-Wallis analysis of variance analysis showed the mean proviral copy number (log10) to be significantly different between groups (p < 0.001) where CD4 counts were grouped as < 200/mm3 (3.4 +/- 1.05 copies), 200-500/mm3 (2.84 +/- 0.93 copies), and > 500/mm3 (1.88 +/- 0.43 copies).(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS following mother-to-child transmission of HIV-2.

Mother-to-child infection with HIV-2 is thought to be rare, and there have been few previous reports of transmission by this route. Reports of morbidity associated with HIV-2 infection in children are also rare. We describe eight children born to mothers who were infected with HIV-2; five developed AIDS, and three were still seropositive at 17-49 months of age. The only apparent route of HIV-2 transmission was from mother to child, except for one child who had been transfused. Three of the children with AIDS died, all having decreased CD4+ lymphocytes and mitogen responses. Further studies are needed to determine the prevalence and natural history of mother-to-child transmission of HIV-2.

PIP: Eight cases of mother-to-child transmission of HIV-2 were documented by ELISA and Western blot in Gambia between January 1988-September 1989 from a hospital-based screening of 205 malnourished children, 864 subjects in a malaria study, 34 patients with probable immunodeficiency and 24 children of 17 HIV-2 seropositive mothers. AIDS was diagnosed by WHO clinical definition. Diagnosis of HIV-2 was made if sera were positive by ELISA and Western blot (LAV Blot2, Diagnostics Pasteur, Marnes-La-Coquette, France) and negative by Wellcozyme I competitive ELISA to HIV-a (Wellcome Diagnostics, Dartford, UK). The children ranged in age from 17 months-5 years, and in ponderal index from 50-90%. 6 had CD4 percentages or counts below the normal range. 7 of the 8 could only have been infected pre- or perinatally, while 1 had been transfused from her mother. The clinical features included 5 with diarrhea 1 month; 3 with Cryptosporidium, 3 with Candida, a pneumonia, an interstitial pneumonia by x-ray, a streptococcus abscess, a staphylococcus abscess, 1 infant with failure to thrive and 1 4-year old who was asymptomatic. This group of patients was more severely affected than a series reported from Guinea Bissau: their mothers also had advanced AIDS in comparison to asymptomatic mothers in the other series. While mother-to-child transmission of HIV-1 occurs in approximately 33% of children of HIV-1 seropositive mothers, these data cannot estimate the actual rate of transmission of HIV-2.

The effects of Plasmodium falciparum malaria on immune control of B lymphocytes in Gambian children.

Children living in hyperendemic malarious regions have high immunoglobulin levels and an increased frequency of Burkitt's lymphoma. In a study of Gambian children which endeavours to explain these findings we showed that acute P. falciparum malaria caused spontaneous activation and growth of their B lymphocytes in vitro. A high proportion of these cells contained Epstein-Barr nuclear antigen (EBNA). In ancillary experiments aimed at explaining these findings. CD4 helper cells from adult donors were destroyed with monoclonal antibody and complement. This manoeuvre resulted in loss of cytotoxic T cell control of their B lymphocytes when infected with Epstein-Barr virus (EBV). In children with acute malaria, both spontaneous immunoglobulin and antibody production by B cells was increased yet CD4 helper cell control over these cells, as measured by responses to pokeweed mitogen, was found to be intact. Spontaneous and concanavalin A-driven lymphocyte proliferation was depressed. We infer from these findings that in patients with P. falciparum malaria loss of cytotoxic T cell control of the EBV in B cells, possibly due to destruction or dysfunction of a subset of CD4 cells responsible for induction of suppressor/cytotoxic CD8 cells, leads to activation and proliferation of foci of B cells containing EBV. The expanded pool and rapid turnover of these cells may increase chances of malignant transformation leading to the genesis of Burkitt's tumor. Partial loss of suppressor mechanisms coupled with normal CD4 helper/inducer activity may result in high serum levels of immunoglobulin which are characteristic of persons living in malarious regions.

Plasmodium falciparum schizont sonic extracts suppress lymphoproliferative responses to mitogens and antigens in malaria-immune adults.

Cellular immune responses to malaria antigens are suppressed during acute Plasmodium falciparum infection, and evidence from both murine and human studies suggests that parasite-derived factors may be directly immunosuppressive. In this study we have shown that P. falciparum schizont sonic extract will suppress in vitro lymphoproliferative responses to purified malaria antigens and other soluble antigens. The degree of suppression appears to correlate with the level of the lymphoproliferative response to the schizont preparation and is correspondingly more marked in malaria-immune donors than in nonimmune individuals. The effect can be transferred with primed mononuclear cells and is partially abrogated by removal of CD8+ lymphocytes. The suppressive component of the schizont preparation is nondialyzable and partially heat labile and comigrates with hemoglobin-derived proteins in the molecular mass range 10 to 20 kilodaltons.

CD8+ T cells inhibit Plasmodium falciparum-induced lymphoproliferation and gamma interferon production in cell preparations from some malaria-immune individuals.

Infection with Plasmodium falciparum induces marked disturbances in normal immunoregulatory functions. Antigen-specific immunosuppression is a feature of acute malaria and has been linked to activation of CD8+ T suppressor cells. Among immune adults, cell-mediated immune responses to malaria antigens are extremely variable when measured in vitro, and there is no obvious relation between responsiveness and resistance to clinical disease. In this study, when CD8+ cells were removed from peripheral blood mononuclear cell preparations obtained from individuals who responded poorly to a soluble malaria antigen preparation, both lymphoproliferation and gamma interferon production were significantly enhanced, but responses to other soluble antigens and mitogen were unaffected. No effect of CD8+ cell depletion was seen in individuals whose undepleted mononuclear cells gave a high response to the malaria antigen. This suggests that for some malaria-exposed individuals, CD8+ cells activated in vitro by exposure to malaria antigens suppress other cellular responses and may obscure the presence of potentially protective immune mechanisms.

Trial of an attenuated bovine rotavirus vaccine (RIT 4237) in Gambian infants.

A randomised, controlled trial of bovine rotavirus vaccine was undertaken in Gambian infants. Three doses were administered, from the age of ten weeks, concurrently with oral or killed polio vaccine. Prevaccination rotavirus neutralising antibody levels were high. 84/185 infants (45%) showed an increase in neutralising antibody titre after receiving rotavirus vaccine, compared with 20/91 (22%) unvaccinated infants. Clinical rotavirus infection was detected in 24/78 (31%) children in the rotavirus/oral polio group, 34/83 (41%) children in the placebo/oral polio group, and 23/92 (25%) children in the rotavirus/killed polio group, giving an overall vaccine efficacy of 33% (95% CI 4-53%). RIT 4237 did not appear to reduce the severity of clinical infections. Most cases (92%) were caused by rotaviruses with short RNA electropherotypes. Serological responses to rotavirus vaccination appeared unaffected by the concurrent administration of oral polio vaccine. Lower types 1 and 3 polio antibody levels were found in children who received oral polio and rotavirus vaccines but the differences were not statistically significant.