Mary Fran McLane

Noninfectious entry of HIV-1 into peripheral and brain macrophages mediated by the mannose receptor

Although protein receptors on the plasma membrane involved in the initial steps of productive HIV-1 infection have been well characterized, little is known about interactions between cellular carbohydrate receptors and HIV-1. Here, we report the involvement of a carbohydrate receptor, the macrophage mannose receptor (MR), and its role in supporting HIV-1 binding and entry. HIV-1 can enter the cytoplasm of human macrophages and microglia as well as murine macrophages by MR, although no subsequent viral replication was observed. Correspondingly, HIV-1 entry into Cos-7 cells after induction of expression of MR by transfection with MR-cDNA did not demonstrate viral replication. Our studies suggest that whereas MR may serve as a binding and an entry site, the MR-mediated pathway does not lead to productive HIV-1 infection. In addition, we report that recombinant HIV-1 gp120 blocks MR-mediated phagocytosis in human and murine alveolar macrophages and microglial cells. Therefore, characterization of the HIV-1 noninfectious MR-mediated phagocytic pathway may foster advances in HIV-1 vaccine design and an improved understanding of HIV-1/AIDS pathogenesis and host defenses.

Noma in children with severe combined immunodeficiency

Three Native American children with severe combined immunodeficiency developed noma, a necrotizing gingivostomatitis not previously reported in this country. The similarity between the clinical findings and those observed in monkeys with simian AIDS prompted us to evaluate our patients and their families for human retroviral infection. Antibodies to HTLV-I or HTLV-III/LAV proteins were not identified in patients nor in their family members. Standard bacterial and viral cultures similarly failed to identify a suspect pathogen.

Apparent Transmission of Human T-Cell Leukemia Virus Type III to a Heterosexual Woman with the Acquired Immunodeficiency Syndrome

A 24-year-old woman developed the acquired immunodeficiency syndrome with lymphadenopathy, oral candidiasis, and Kaposis sarcoma. Her only known risk factor for the syndrome was sexual contact with an asymptomatic Haitian man. The woman had serologic evidence for infection with human T-cell lymphotropic virus type III, and this virus was recovered from the saliva of her sexual partner. Epidemiologic and virologic studies of the cases of such patients provide further evidence of a primary pathogenetic role for this retrovirus in the acquired immunodeficiency syndrome.

Antibody to Human T-Cell Leukemia Virus Membrane Antigens, Beta2-Microglobulin Levels, and Thymosin Alpha1 Levels in Hemophiliacs and Their Spouses

Recently, antibodies to human T-cell leukemia virus membrane antigens (HTLV-MA) and elevated levels of beta 2-microglobulin and thymosin alpha 1 have been found with high frequency in patients with the acquired immunodeficiency syndrome. Prospective studies of asymptomatic persons at high risk for this syndrome will ascertain whether any of these findings is a predictive marker for the disease. In this study, antibodies to HTLV-MA, beta 2-microglobulin levels, and thymosin alpha 1 levels were determined for a group of asymptomatic adult hemophiliacs and their wives. Five of thirty-nine hemophiliacs had HTLV-MA antibody, compared with none of 21 wives tested. The mean beta 2-microglobulin level for hemophiliacs was significantly higher than the control value (p less than 0.001), whereas the wives had a normal mean value. The mean thymosin alpha 1 values were normal for hemophiliacs and their wives; however, 3 of 22 hemophiliacs and 1 of 16 wives had abnormally high levels. Whether any of these abnormalities correlate with subsequent development of the acquired immunodeficiency syndrome will be ascertained by longitudinal follow-up of this population.

Ribavirin Treatment of the Acquired Immunodeficiency Syndrome (AIDS) and the Acquired-Immunodeficiency-Syndrome-Related Complex (ARC): A Phase 1 Study Shows Transient Clinical Improvement Associated with Suppression of the Human Immunodeficiency Virus and Enhanced Lymphocyte Proliferation

STUDY OBJECTIVE To assess safety, tolerance, and the clinical and laboratory effects of oral ribavirin in patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. DESIGN Three uncontrolled phase I trials of increasing duration: 14 days, 8 weeks, and 12 months. SETTING Outpatient clinic of a university-referral hospital. PATIENTS All patients were antibody-positive for the human immunodeficiency virus (HIV) by radioimmunoprecipitation assay, all had recovered from Pneumocystis carinii pneumonia, and none had Kaposi sarcoma at entry. Nine of ten patients with AIDS had less than 100 CD4+ lymphocytes/mm3 at entry and all patients with the AIDS-related complex had fewer than 200 CD4+ lymphocytes/mm3. Five patients with AIDS and five with the AIDS-related complex entered the 14-day trial. All but two patients with AIDS went on to the 8-week trial, along with seven additional patients with AIDS. Five surviving patients with AIDS and 3 patients with the AIDS-related complex went on to the 1-year study. INTERVENTIONS Oral ribavirin, 1200 mg twice daily for 3 days was given, followed by 300 mg twice daily for 11 days. During an 8-week trial, a loading dose of oral ribavirin was administered for 3 days, followed by a dose of 300 mg twice daily for 8 weeks. Prolonged regimen of a 3-day loading dose was given, followed by a dose of 300 mg twice daily for 1 year. MEASUREMENTS AND MAIN RESULTS Ribavirin treatment was well tolerated, with anemia requiring transfusion in one of the ten patients with AIDS receiving the drug for 8 weeks; no other significant toxicity occurred. Six of nine patients initially positive for HIV-1 in blood became negative during ribavirin treatment. Six of nine patients with AIDS had a twofold improvement in lymphoproliferative response to at least one lectin with ribavirin treatment. Mean survival from first episode of P. carinii pneumonia was 17.3 months in patients with AIDS receiving 8 weeks of ribavirin and 21.2 months in patients with AIDS receiving prolonged treatment. CONCLUSIONS Oral ribavirin, 600 mg daily, was well tolerated and safe in the patients with severe AIDS and the AIDS-related complex. Ribavirin therapy merits extensive evaluation in a multicenter controlled trial to assess its efficacy.

Phylogenetic Relatedness of Circulating HIV-1C Variants in Mochudi, Botswana

Background Determining patterns of HIV transmission is increasingly important for the most efficient use of modern prevention interventions. HIV phylogeny can provide a better understanding of the mechanisms underlying HIV transmission networks in communities. Methods To reconstruct the structure and dynamics of a local HIV/AIDS epidemic, the phylogenetic relatedness of HIV-1 subtype C env sequences obtained from 785 HIV-infected community residents in the northeastern sector of Mochudi, Botswana, during 2010–2013 was estimated. The genotyping coverage was estimated at 44%. Clusters were defined based on relatedness of HIV-1C env sequences and bootstrap support of splits. Results The overall proportion of clustered HIV-1C env sequences was 19.1% (95% CI 17.5% to 20.8%). The proportion of clustered sequences from Mochudi was significantly higher than the proportion of non-Mochudi sequences that clustered, 27.0% vs. 14.7% (p = 5.8E-12; Fisher exact test). The majority of clustered Mochudi sequences (90.1%; 95% CI 85.1% to 93.6%) were found in the Mochudi-unique clusters. None of the sequences from Mochudi clustered with any of the 1,244 non-Botswana HIV-1C sequences. At least 83 distinct HIV-1C variants, or chains of HIV transmission, in Mochudi were enumerated, and their sequence signatures were reconstructed. Seven of 20 genotyped seroconverters were found in 7 distinct clusters. Conclusions The study provides essential characteristics of the HIV transmission network in a community in Botswana, suggests the importance of high sampling coverage, and highlights the need for broad HIV genotyping to determine the spread of community-unique and community-mixed viral variants circulating in local epidemics. The proposed methodology of cluster analysis enumerates circulating HIV variants and can work well for surveillance of HIV transmission networks. HIV genotyping at the community level can help to optimize and balance HIV prevention strategies in trials and combined intervention packages.

Frequent Intra-Subtype Recombination among HIV-1 Circulating in Tanzania

The study estimated the prevalence of HIV-1 intra-subtype recombinant variants among female bar and hotel workers in Tanzania. While intra-subtype recombination occurs in HIV-1, it is generally underestimated. HIV-1 env gp120 V1-C5 quasispecies from 45 subjects were generated by single-genome amplification and sequencing (median (IQR) of 38 (28–50) sequences per subject). Recombination analysis was performed using seven methods implemented within the recombination detection program version 3, RDP3. HIV-1 sequences were considered recombinant if recombination signals were detected by at least three methods with p-values of ≤0.05 after Bonferroni correction for multiple comparisons. HIV-1 in 38 (84%) subjects showed evidence for intra-subtype recombination including 22 with HIV-1 subtype A1, 13 with HIV-1 subtype C, and 3 with HIV-1 subtype D. The distribution of intra-patient recombination breakpoints suggested ongoing recombination and showed selective enrichment of recombinant variants in 23 (60%) subjects. The number of subjects with evidence of intra-subtype recombination increased from 29 (69%) to 36 (82%) over one year of follow-up, although the increase did not reach statistical significance. Adjustment for intra-subtype recombination is important for the analysis of multiplicity of HIV infection. This is the first report of high prevalence of intra-subtype recombination in the HIV/AIDS epidemic in Tanzania, a region where multiple HIV-1 subtypes co-circulate. HIV-1 intra-subtype recombination increases viral diversity and presents additional challenges for HIV-1 vaccine design.

HIV-1 pol diversity among female bar and hotel workers in Northern Tanzania.

A national ART program was launched in Tanzania in October 2004. Due to the existence of multiple HIV-1 subtypes and recombinant viruses co-circulating in Tanzania, it is important to monitor rates of drug resistance. The present study determined the prevalence of HIV-1 drug resistance mutations among ART-naive female bar and hotel workers, a high-risk population for HIV-1 infection in Moshi, Tanzania. A partial HIV-1 pol gene was analyzed by single-genome amplification and sequencing in 45 subjects (622 pol sequences total; median number of sequences per subject, 13; IQR 5–20) in samples collected in 2005. The prevalence of HIV-1 subtypes A1, C, and D, and inter-subtype recombinant viruses, was 36%, 29%, 9% and 27%, respectively. Thirteen different recombination patterns included D/A1/D, C/A1, A1/C/A1, A1/U/A1, C/U/A1, C/A1, U/D/U, D/A1/D, A1/C, A1/C, A2/C/A2, CRF10_CD/C/CRF10_CD and CRF35_AD/A1/CRF35_AD. CRF35_AD was identified in Tanzania for the first time. All recombinant viruses in this study were unique, suggesting ongoing recombination processes among circulating HIV-1 variants. The prevalence of multiple infections in this population was 16% (n = 7). Primary HIV-1 drug resistance mutations to RT inhibitors were identified in three (7%) subjects (K65R plus Y181C; N60D; and V106M). In some subjects, polymorphisms were observed at the RT positions 41, 69, 75, 98, 101, 179, 190, and 215. Secondary mutations associated with NNRTIs were observed at the RT positions 90 (7%) and 138 (6%). In the protease gene, three subjects (7%) had M46I/L mutations. All subjects in this study had HIV-1 subtype-specific natural polymorphisms at positions 36, 69, 89 and 93 that are associated with drug resistance in HIV-1 subtype B. These results suggested that HIV-1 drug resistance mutations and natural polymorphisms existed in this population before the initiation of the national ART program. With increasing use of ARV, these results highlight the importance of drug resistance monitoring in Tanzania.

Evolutionary gamut of in vivo Gag substitutions during early HIV-1 subtype C infection

Two analyses of HIV-1 subtype C Gag quasispecies were performed in a prospective cohort of 42 acutely and recently infected individuals by SGA on viral RNA/proviral DNA templates. First, in vivo Gag substitutions were assessed in relation to the HIV-1C consensus sequence, which revealed that 29.3% of detected amino acid substitutions can be classified as reversions to subtype consensus, 61.3% as forward substitutions from subtype consensus, and 9.3% as polymorphisms not associated with the subtype consensus sequence. Second, the proportion, dynamics, and relationships within individual pools of viral quasispecies were analyzed. Among reverse substitutions, 16.1% were minor, 11.0% transient, 13.6% dominant, and 59.2% fixed. In contrast, 31.6% of forward substitutions were minor, 59.3% transient, 3.8% dominant, and 5.3% fixed. The distinct patterns in the spectrum and dynamics of reverse and forward Gag substitutions suggest that these differences should be considered in HIV-1 evolutionary studies and analyses of viral mutational pathways.

Correction for Novitsky et al., Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering

Volume 53, no. 8, p. [2581–2592][1], 2015. Table S1 in the supplemental material: The sequence for primer OFM19 was incorrect; it was missing the triplet ATT. Revised supplemental material is posted at . [1]: /lookup/doi/10.1128/JCM.