Laurent Bélec

Interactions between Herpes Simplex Virus Type 2 and Human Immunodeficiency Virus Type 1 Infection in African Women: Opportunities for Intervention

Sexually transmitted diseases (STDs) are cofactors for human immunodeficiency virus (HIV) transmission, but the specific role of herpes simplex virus type 2 (HSV-2) is unclear. This study aimed to examine the in vivo relationships between HSV-2 and HIV-1 in 300 women in Bangui, Central African Republic. Sera were tested for syphilis, HIV-1, HSV-2 antibody, and levels of vitamins A and E. Genital specimens were tested for other STDs. HSV-2 DNA and HIV-1 RNA were quantified in cervicovaginal lavage. The prevalences of HSV-2 antibody (91% vs. 78%, P=.02), HSV-2 shedding (43% vs. 22%, P=. 003), and levels of HSV-2 DNA (P=.01) were all significantly higher among HIV-1-seropositive than among HIV-1-seronegative women. There was a significant correlation between genital HIV-1 RNA and HSV-2 DNA levels (P=.02) among the 23 women who were shedding HSV-2 DNA. If confirmed, such associations highlight the urgent need for HSV-2 control measures in populations at high risk of both infections.

Long-Term Clinical Outcome of Human Immunodeficiency Virus–Infected Patients with Discordant Immunologic and Virologic Responses to a Protease Inhibitor–Containing Regimen

Within a prospective cohort of 150 human immunodeficiency virus (HIV)-infected patients who began first-line protease inhibitor therapy in 1996, the outcome of 42 patients with discrepant virologic and immunologic responses to antiretroviral treatment at 12 months was analyzed at 30 months of treatment. The incidence of AIDS-defining events and deaths (14%) in the group of patients with immunologic responses in the absence of a virologic response was higher than that in full-responder patients (2%); yet, the incidence in this group was lower than that in patients with no immunologic response, despite a virologic response (21%), and was lower than that in patients without an immunologic or virologic response (67%; P<.0001, log-rank test). Differences in outcome were significant (relative risk, 6.9; 95% confidence interval, 1.9-39.3) when factors for progression were compared with those of responder patients. The results support the relevance of the CD4 cell marker over plasma HIV load for predicting clinical outcome in patients who do not achieve full immunologic and virologic responses.

Cervicovaginal Secretory Antibodies to Human Immunodeficiency Virus Type 1 (HIV-1) that Block Viral Transcytosis through Tight Epithelial Barriers in Highly Exposed HIV-1–Seronegative African Women

Antibodies to human immunodeficiency virus (HIV) of the IgA, IgG, and IgM isotypes and high levels of the HIV suppressive beta-chemokine RANTES (regulated on activation, normally T cell expressed and secreted) were found in the cervicovaginal secretions (CVSs) of 7.5% of 342 multiply and repeatedly exposed African HIV-seronegative female sex workers. The antibodies are part of a local compartmentalized secretory immune response to HIV, since they are present in vaginal fluids that are free of contaminating semen. Cervicovaginal antibodies showed a reproducible pattern of reactivity restricted to gp160 and p24. Locally produced anti-env antibodies exhibit reactivity toward the neutralizing ELDKWA epitope of gp41. Study results show that antibodies purified from CVSs block the transcytosis of cell-associated HIV through a tight epithelial monolayer in vitro. These findings suggest that genital resistance to HIV may involve HIV-specific cervicovaginal antibody responses in a minority of highly exposed HIV-seronegative women in association with other protecting factors, such as local production of HIV-suppressive chemokines.

Selection of Drug-Resistant Variants in the Female Genital Tract of Human Immunodeficiency Virus Type 1-Infected Women Receiving Antiretroviral Therapy

We investigated human immunodeficiency virus (HIV) type 1 RNA, proviral DNA, and antiretroviral drug-resistant variants in cervicovaginal secretions of HIV-1-infected women receiving antiretroviral therapy. The prevalence of detectable HIV-1 RNA in genital secretions was inversely related to the number of antiretroviral drugs taken by the patients. Proviral DNA was detected in approximately half of all samples of cervicovaginal secretions from HIV-1-infected women, regardless of the presence or absence of HIV-1 RNA in cervicovaginal secretions and of the antiretroviral regimen. In cervicovaginal secretions of most women with persisting genital viral replication, HIV variants exhibiting mutations associated with drug resistance against protease and reverse-transcriptase pol genes were found. Our observations indicate that antiretroviral therapy is not effective in purging the female genital tract of cell-associated provirus and that antiretroviral drugs that penetrate the female genital tract at suboptimal concentrations exert a potent selective pressure on genital HIV variants when local replication of free HIV-1 RNA persists.

Secretory Anti-Human Immunodeficiency Virus (HIV) Antibodies in Colostrum and Breast Milk Are Not a Major Determinant of the Protection of Early Postnatal Transmission of HIV

The immune response to human immunodeficiency virus (HIV) type 1 was evaluated in breast milk from HIV-infected African mothers who had transmitted and those who had not transmitted HIV to their children through breast-feeding. The levels, specific activities against gp160 and 2 HIV-derived peptides from gp41 and gp120 (V3 loop), and inhibitory activity toward viral transcytosis in vitro of secretory IgA (S-IgA) and IgG purified from breast milk were investigated in 8 transmitting mothers and 18 nontransmitting mothers. S-IgA and IgG antibodies to gp160 and to peptides were found in all breast milk samples. The specific activities of S-IgA and IgG to gp160 and peptides were similar between transmitting and nontransmitting mothers. No difference of the capacity of S-IgA and IgG to block HIV transcytosis in vitro was found between the 2 groups. These results suggest that humoral mucosal immunity to HIV does not appear as a predominant factor for protection against viral transmission through breast milk.

High prevalence in Central Africa of blood donors who are potentially infectious for human herpesvirus 8

BACKGROUND: In western countries, the transmission of human herpesvirus 8 (HHV‐8) via blood transfusion has been recently postulated. In sub‐ Saharan African, the incidence of HHV‐8‐associated Kaposis sarcoma and the seroprevalence for HHV‐8 in autochthonous populations are high.

High Levels of Drug-Resistant Human Immunodeficiency Virus Variants in Patients Exhibiting Increasing CD4+ T Cell Counts Despite Virologic Failure of Protease Inhibitor—Containing Antiretroviral Combination Therapy

The genotypic mutations associated with indinavir resistance were analyzed in 27 patients who exhibited sustained CD4+ T cell responses to highly active antiretroviral therapy (HAART), despite virologic failure of treatment. After 12 months of HAART, 1 or 2 primary resistance mutations had occurred in 18 (66%) of the patients, and secondary mutations had accumulated in 22 (88%) of the patients. The number and patterns of mutations in the patients who exhibited discrepant responses to HAART did not differ from those observed in patients who exhibited immunologic and virologic failure to therapy. Results indicate that many patients have prolonged immunologic benefits, despite the development of virologic failure and protease inhibitor mutations. The clinical course of this group of patients calls into question the relevance of genotypic resistance and plasma human immunodeficiency virus RNA level as surrogate markers in patients receiving HAART.

Independent Levels of Cell-Free and Cell-Associated Human Immunodeficiency Virus–1 in Genital-Tract Secretions of Clinically Asymptomatic, Treatment-Naive African Women

Using ultrasensitive polymerase chain reaction-based techniques, we assessed levels of cell-free and cell-associated human immunodeficiency virus (HIV)-1 in paired blood and genital samples of 30 clinically asymptomatic, treatment-naive women. Levels of HIV-1 RNA in cervicovaginal-lavage samples were positively correlated with those in plasma samples (r=.50; P=.008), whereas levels of HIV-1 DNA in genital samples were loosely correlated with those in blood samples (r=.31; P=.041). In plasma of peripheral blood, levels of HIV-1 DNA were positively correlated with those of HIV-1 RNA (r=.64; P<.001), whereas no correlation between HIV-1 DNA and HIV-1 RNA was evident in genital secretions. Our results indicate that levels of HIV-1 RNA and HIV-1 DNA are unrelated in the genital tracts of treatment-naive women and suggest that the level of genital HIV-1 RNA is influenced by systemic viral replication-in contrast to genital HIV-1 provirus, which may be influenced as well by local cofactors triggering the migration of HIV-infected cells originating from the cervicovaginal submucosa. These features may be relevant for an understanding of HIV-1 transmission in heterosexual individuals.

The cumulative occurrence of resistance mutations in the HIV-1 protease gene is associated with failure of salvage therapy with ritonavir and saquinavir in protease inhibitor-experienced patients.

Salvage therapy with ritonavir (RTV) and saquinavir (SQV) failed to achieve virological and immunological improvement in 24 HIV-infected patients who discontinued triple therapy with RTV or indinavir (IDV) because of failure or intolerance to treatment. Changes in the HIV-1 protease gene sequence were analyzed prospectively in 14 patients. No primary protease mutation was found prior to the use of protease inhibitors. After 7 months of treatment with IDV or RTV, primary resistance mutations at codons pol 46 and/or pol 82 were observed in 11 of 13 patients. After 16 weeks on RTV-SQV, novel primary mutations related to SQV emerged in 7 of 13 patients, together with an increase in the number of secondary resistance mutations. Our observations indicate that the cumulative occurrence of resistance mutations in the protease gene was associated with failure of antiretroviral therapy. The presence of mutations to a first protease inhibitor may represent a risk factor for the failure of a subsequent treatment with a second line protease inhibitor.

Hepatitis C virus RNA viremia in Central Africa.

of age. Sex was not significantly associated (mean male to female sex ratio was 32.4:18 for S. typhi and 15.8:10.6 for S. paratyphi A). S. typhi has become increasingly sensitive to amoxycillin, chloramphenicol, and gentamicin, increasing from 75.1% in 1994 to 96.6% in 1998 for amoxycillin, from 71.9% in 1994 to 91.6% in 1998 for chloramphenicol, and from 96.4% to 100% for gentamicin. S. paratyphi A strains have remained uniformly sensitive (100%) to all antibiotics (amoxycillin, chloramphenicol, and gentamicin, as well as ciprofloxacin and ceftriaxone) used in the treatment of enteric fever. In light of reports of multidrug resistance in S. typhi, especially to quinolones, continued surveillance and monitoring of antimicrobial sensitivity of S. paratyphi A strains are needed. The increase in proportion of S. paratyphi A cases, which may be due to a high degree of clinical suspicion (with mild fever cases investigated for enteric fever), changing host susceptibility, or even change in the virulence of the organism, should be further investigated.