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In human immunodeficiency virus type 1 (HIV-1) subtype B, CXCR4 coreceptor use ranges from ∼20% in early infection to ∼50% in advanced disease. Coreceptor use by non-subtype B HIV is less well characterized. We studied coreceptor tropism of subtype A and D HIV-1 collected from 68 pregnant, antiretroviral drug-naive Ugandan women (HIVNET 012 trial). None of 33 subtype A or 10 A/D-recombinant viruses used the CXCR4 coreceptor. In contrast, nine (36%) of 25 subtype D viruses used both CXCR4 and CCR5 coreceptors. Clonal analyses of the nine subtype D samples with dual or mixed tropism revealed heterogeneous viral populations comprised of X4-, R5-, and dual-tropic HIV-1 variants. In five of the six samples with dual-tropic strains, V3 loop sequences of dual-tropic clones were identical to those of cocirculating R5-tropic clones, indicating the presence of CXCR4 tropism determinants outside of the V3 loop. These dual-tropic variants with R5-tropic-like V3 loops, which we designated “dual-R,” use CCR5 much more efficiently than CXCR4, in contrast to dual-tropic clones with X4-tropic-like V3 loops (“dual-X”). These observations have implications for pathogenesis and treatment of subtype D-infected individuals, for the association between V3 sequence and coreceptor tropism phenotype, and for understanding potential mechanisms of evolution from exclusive CCR5 use to efficient CXCR4 use by subtype D HIV-1.

Summary Background Identification of economical interventions to decrease HIV-1 transmission to children is an urgent public-health priority in sub-Saharan Africa. We assessed the cost effectiveness of the HIVNET 012 nevirapine regimen. Methods We assessed cost effectiveness in a hypothetical cohort of 20 000 pregnant women in sub-Saharan Africa. Our main outcome measures were programme cost, paediatric HIV-1 cases averted, cost per case averted, and cost per disability-adjusted life-year (DALY). We compared HIVNET 012 with other short-course antiretroviral regimens. We also compared two implementation strategies: counselling and HIV-1 testing before treatment (targeted treatment), or nevirapine for all pregnant women (universal treatment, no counselling and testing). We did univariate and multivariate sensitivity analyses. Findings For universal treatment with 30% HIV-1 seroprevalence, the HIVNET 012 regimen would avert 603 cases of HIV-1 in babies, cost US$83 333, and generate 15 862 DALYs. The associated cost-effectiveness ratios were $138 per case averted or $5·25 per DALY. At 15% seroprevalence, the universal treatment option would cost $83 333 and avert 302 cases at $276 per case averted or $10·51 per DALY. For targeted treatment at 30% seroprevalence, HIVNET 012 would cost $141 922 and avert 476 cases at $298 per case averted or $11·29 per DALY. With seroprevalence higher than 3·0% for universal and 4·5% for targeted treatment, the HIVNET 012 regimen was likely to be as cost effective as other public-health interventions. The cost effectiveness of HIVNET 012 was robust under a wide range of parameters in the sensitivity analysis. Interpretation The HIVNET 012 regimen can be highly cost-effective in high seroprevalence settings. In lower seroprevalence areas, when multidose regimens are not cost effective, nevirapine therapy could have a major public-health impact at a reasonable cost.

Since cellular activation is required for replication of human immunodeficiency virus type 1 (HIV-1), the capacity of alveolar macrophages (AM) from smokers, which are relatively activated, and nonsmokers to support the production of HIV-1JR-FL was examined. Peak HIV-1 p24 antigen level in culture supernatants of infected AM from 13 smokers was significantly higher than that of 13 nonsmokers: 31,394 +/- 8295 versus 7037 +/- 2550 pg/mL (mean +/- SE; P < .002). This difference could not be explained on the basis of viral entry, extent of reverse transcription, or release of monokines, including tumor necrosis factor-alpha, interleukin-1 beta or -6, and granulocyte-macrophage colony-stimulating factor. HIV-1 production by blood monocytes from smokers and nonsmokers infected in vitro was negligible. Thus, cigarette smoking selectively increases the susceptibility of AM to productive infection with HIV-1. This finding provides a biologic plausibility to observations that smoking may enhance the progression of AIDS.

BACKGROUND:Accurate incidence estimates are needed for surveillance of the HIV epidemic. HIV surveillance occurs at maternal-child health clinics, but it is not known if pregnancy affects HIV incidence testing. METHODS:We used the BED capture immunoassay (BED) and an antibody avidity assay to test longitudinal samples from 51 HIV-infected Ugandan women infected with subtype A, C, D and intersubtype recombinant HIV who were enrolled in the HIVNET 012 trial (37 baseline samples collected near the time of delivery and 135 follow-up samples collected 3, 4 or 5 years later). Nineteen of 51 women were also pregnant at the time of one or more of the follow-up visits. The BED assay was performed according to the manufacturer's instructions. The avidity assay was performed using a Genetic Systems HIV-1/HIV-2 + O EIA using 0.1M diethylamine as the chaotropic agent. RESULTS:During the HIVNET 012 follow-up study, there was no difference in normalized optical density values (OD-n) obtained with the BED assay or in the avidity test results (%) when women were pregnant (n = 20 results) compared to those obtained when women were not pregnant (n = 115; for BED: p = 0.9, generalized estimating equations model; for avidity: p = 0.7, Wilcoxon rank sum). In addition, BED and avidity results were almost exactly the same in longitudinal samples from the 18 women who were pregnant at only one study visit during the follow-up study (p = 0.6, paired t-test). CONCLUSIONS:These results from 51 Ugandan women suggest that any changes in the antibody response to HIV infection that occur during pregnancy are not sufficient to alter results obtained with the BED and avidity assays. Confirmation with larger studies and with other HIV subtypes is needed.

Two non-isotopic polymerase chain reaction (PCR) methods were evaluated by testing blood from 41 HIV-1-seropositive and 16 HIV-1-seronegative Ugandan mothers and 56 of their children (aged 0.5-15.0 months). Amplification of HIV-1 sequences was performed in duplicate using a biotinylated primer pair to the gag region (SK 462-431) and nested primer pairs (JA 17-20) to the pol region of HIV-1. gag sequences were hybridized using a microtiter plate coated with the SK 102 probe followed by colorimetric detection using an avidin-horseradish peroxidase conjugate and tetramethylbenzidine/peroxide substrate. pol sequences were detected on agarose gel stained with ethidium bromide. Results of HIV-1 PCR analysis showed that 40 out of 41 (98%) seropositive mothers and 10 out of 29 (34%) seropositive children had detectable HIV-1 gag and pol sequences. None of the 16 seronegative mothers nor 27 seronegative or Western blot-indeterminate children had detectable HIV-1 sequences. Our results suggest that non-isotopic PCR methods are sensitive, specific, and potentially useful in the early diagnosis of HIV-1 infection in developed and developing countries.

K103N is frequently detected in HIV-infected women after single dose (SD) nevirapine (NVP). K103N-containing variants were detected more frequently by the ViroSeq HIV-1 Genotyping System in women with subtype C (69.2%) than subtypes A (19.4%, p0.0001) or D (36.1%, p0.0001). K103N-containing variants were also detected more frequently and at higher levels in women with subtype C by the LigAmp assay. In this report, we analyzed samples collected prior to or within hours after SD NVP administration from antiretroviral drug-naive African women with subtypes A, C, and D. Only 1/254 samples had an NVP resistance mutation detected with the ViroSeq system, and only 4/236 samples had K103N detected at0.5% with the LigAmp assay [2/110 (1.8%) with subtype A, 1/46 (2.2%) with subtype C, and 1/80 (1.3%) with subtype D] (p = 0.92). We did not detect significant differences in the pre-NVP frequency of NVP resistance mutations or the pre-NVP levels of K103N-containing variants in women with subtypes A, C, and D that explain the dramatic subtype-based differences in emergence of HIV-1 variants with these mutations after SD NVP exposure.

To compare the rate of mother-to-child transmission (MTCT) in women with subtype A versus D HIV-1 who received single-dose nevirapine (NVP).The MTCT rates were compared in women with subtype A versus D at birth and at 8 weeks and 18 months of age of the infants. The rate of late MTCT (after 8 weeks of age) was also analyzed.HIV-1 subtypes were determined for 300 of 306 women who received NVP in the HIV Network for Prevention Trials 012 study (158 women with subtype A and 105 women with subtype D). Infant infection status was known for 297 women. The cumulative rate of MTCT at 18 months was 13.2% for subtype A and 18.3% for subtype D (P=0.34). The rate of late transmission was 3.8% for subtype A and 7.6% for subtype D (P=0.28). Maternal baseline viral load was a significant predictor of MTCT, but maternal baseline CD4 cell count and subtype were not.No significant difference was observed in the rate of MTCT in women with subtype A versus D. There was a trend toward a higher rate of MTCT among women with subtype D, however, which was also apparent among women whose infants were infected after 8 weeks of age.

Background. The neurodevelopmental outcomes of human immunodeficiency virus type 1 (HIV-1)-infected Ugandan infants of nondrug-using mothers were studied using controlled, prospective methodology. Method. The sample of 436 full-term infants included 79 HIV-infected infants of HIV-1-infected mothers, 241 uninfected infants of HIV-1-infected mothers (seroreverters), and 116 uninfected infants born to HIV-negative mothers. Neurologic status, information processing ability, and motor and mental development were assessed from 6 to 24 months of age. Observations of caretaker-child interaction and home environments were made at 6 and 12 months. All evaluators were blinded to the HIV status of the child and family. Results. Compared with seroreverters and uninfected infants, HIV-infected infants demonstrated greater deficits in motor development and neurologic status, and more frequent and earlier onset of motor and neurologic abnormalities. Compared with controls, HIV-infected infants had more abnormalities in mental development at 6 and 18 months and an earlier onset of abnormalities. By 12 months, 30% of HIV-infected infants demonstrated motor abnormalities and 26% cognitive abnormalities as compared with 11% and 6% among seroreverters and 5% and 6% among seronegative infants. HIV-infected infants (62%) demonstrated a higher probability of developing an abnormal neurologic examination by 12 months, compared with seroreverters (17%) or seronegative infants (15%). Information-processing abilities did not differ as a function of HIV infection. Home environments and infants' interactions with caretakers were similar across groups. Conclusion. We conclude that HIV infection results in more frequent and earlier abnormalities in infants' neurologic status and motor development that are not attributable to other biological and environmental risk factors. More frequent mental developmental abnormalities were evident at several ages. However, information-processing abilities, such as recognition memory, may be spared from HIV-related deficits.

The mechanism of uptake of human immunodeficiency virus-1 (HIV-1) into alveolar macrophages (AM), freshly isolated blood monocytes (MN), and cultured MN (CM) was investigated focusing on the role of CD4 and of surfactant-associated protein A (SP-A). By radioimmunoassay which obviated the problems of auto- and nonspecific fluorescence of more differentiated macrophages, each of the macrophage populations studied expressed CD4. Semiquantitative polymerase chain reaction was performed to assess uptake of HIV-1(JR-FL) into cells. OKT4a (directed against CD4) blocked uptake of HIV-1 into CM, AM, and MN by 67 to 100%. OKT4 (directed against another epitope of CD4) had a smaller and less consistent effect (0-90%), and control antibodies showed minimal effects and only at supersaturating concentrations. SP-A had no effect on uptake of HIV-1 into AM. SP-A also had no consistent effect on production of HIV-1(JR-FL) by AM infected in vitro (p24 antigen ELISA). Thus CD4 is the major receptor for HIV-1 in mononuclear phagocytes, including AM, and SP-A does not modulate entry.