Generation of lineage-related, mucosally transmissible subtype C R5 simian-human immunodeficiency viruses capable of AIDS development, induction of neurological disease, and coreceptor switching in rhesus macaques.

Most human immunodeficiency virus (HIV) transmissions are initiated with CCR5 (R5)-using viruses across mucosal surfaces, with the majority in regions where HIV type 1 (HIV-1) clade C predominates. Mucosally transmissible, highly replication competent, pathogenic R5 simian-human immunodeficiency viruses (SHIVs) encoding biologically relevant clade C envelopes are therefore needed as challenge viruses in vaccine efficacy studies with nonhuman primates. Here we describe the generation of three lineage-related subtype C SHIVs through four successive rapid transfers in rhesus macaques of SHIVC109F.PB4, a molecular clone expressing the soluble-CD4 (sCD4)-sensitive CCR5-tropic clade C envelope of a recently infected subject in Zambia. The viruses differed in their monkey passage histories and neutralization sensitivities but remained R5 tropic. SHIVC109P3 and SHIVC109P3N were recovered from a passage-3 rapid-progressor animal during chronic infection (24 weeks postinfection [wpi]) and at end-stage disease (34 wpi), respectively, and are classified as tier 1B strains, whereas SHIVC109P4 was recovered from a passage-4 normal-progressor macaque at 22 wpi and is a tier 2 virus, more difficult to neutralize. All three viruses were transmitted efficiently via intrarectal inoculation, reaching peak viral loads of 10(7) to 10(9) RNA copies/ml plasma and establishing viremia at various set points. Notably, one of seven (GC98) and two of six (CL31, FI08) SHIVC109P3- and SHIVC109P3N-infected macaques, respectively, progressed to AIDS, with neuropathologies observed in GC98 and FI08, as well as coreceptor switching in the latter. These findings support the use of these new SHIVC109F.PB4-derived viruses to study the immunopathology of HIV-1 clade C infection and to evaluate envelope-based AIDS vaccines in nonhuman primates.

Mucosal transmissibility, disease induction and coreceptor switching of R5 SHIVSF162P3N molecular clones in rhesus macaques.

BACKGROUND: Mucosally transmissible and pathogenic CCR5 (R5)-tropic simian-human immunodeficiency virus (SHIV) molecular clones are useful reagents to identity neutralization escape in HIV-1 vaccine experiments and to study the envelope evolutionary process and mechanistic basis for coreceptor switch during the course of natural infection. RESULTS: We observed progression to AIDS in rhesus macaques infected intrarectally with molecular clones of the pathogenic R5 SHIVSF162P3N isolate. Expansion to CXCR4 usage was documented in one diseased macaque that mounted a neutralizing antibody response and in another that failed to do so, with the latter displaying a rapid progressor phenotype. V3 loop envelop glycoprotein gp120 sequence changes that are predictive of a CXCR4 (X4)-using phenotype in HIV-1 subtype B primary isolates, specifically basic amino acid substations at positions 11 (S11R), 24 (G24R) and 25 (D25K) of the loop were detected in the two infected macaques. Functional assays showed that envelopes with V3 S11R or D25K mutation were dual-tropic, infecting CD4+ target cells that expressed either the CCR5 or CXCR4 coreceptor. And, consistent with findings of coreceptor switching in macaques infected with the pathogenic isolate, CXCR4-using variant was first detected in the lymph node of the chronically infected rhesus monkey several weeks prior to its presence in peripheral blood. Moreover, X4 emergence in this macaque coincided with persistent peripheral CD4+ T cell loss and a decline in neutralizing antibody titer that are suggestive of immune deterioration, with macrophages as the major virus-producing cells at the end-stage of disease. CONCLUSIONS: The data showed that molecular clones derived from the R5 SHIVSF162P3N isolate are mucosally transmissible and induced disease in a manner similar to that observed in HIV-1 infected individuals, providing a relevant and useful animal infection model for in-depth analyses of host selection pressures and the env evolutionary changes that influence disease outcome, coreceptor switching and vaccine escape.

Employment preferences of healthcare workers in South Africa: Findings from a discrete choice experiment.

There is a maldistribution of human resources for health globally, with many Lower- and Middle-Income Countries experiencing significant shortages. We examined healthcare workers' job preferences in South Africa to identify factors which potentially influence employment decisions. A discrete choice experiment was conducted among 855 South African healthcare workers critical to its national HIV testing and treatment programs. Job characteristics included workload, workplace culture, availability of equipment, training opportunities, sector and facility type, location, salary and benefits. Main effects analysis was conducted using fixed effects logistic regression. Interaction effects identified divergence in preferences. Heavy workload (OR = 0.78; 95% C.I. 0.74-0.83), poor workplace culture (odds ratio 0.66; 95% C.I. 0.62-0.69), insufficient availability of equipment (OR = 0.67; 95% C.I. 0.63-0.70) and infrequent training opportunities (OR = 0.75; 95% C.I. 0.71-0.80) had large, significant effects on worker preferences. An increase in salary of 20% (OR = 1.29; 95% C.I. 1.16-1.44) had a positive effect on preferences, while a salary decrease of 20% (OR = 0.55; 95% C.I. 0.49-0.60) had a strong negative effect. Benefits packages had large positive effects on preferences: respondents were twice as likely to choose a job that included medical aid, pension and housing contributions worth 40% of salary (OR = 2.06; 95% C.I. 1.87-2.26), holding all else constant. Although salary was important across all cadres, benefits packages had larger effects on job preferences than equivalent salary increases. Improving working conditions is critical to attracting and retaining appropriate health cadres responsible for the country's HIV services, especially in the public sector and underserved, often rural, communities. Crucially, our evidence suggests that factors amenable to improvement such as workplace conditions and remuneration packages have a greater influence on healthcare workers employment decisions than employment sector or location.

Determinants of late antenatal care presentation in rural and peri-urban communities in South Africa: A cross-sectional study.

OBJECTIVE: To investigate and compare determinates for delayed first presentation to antenatal care (ANC) services. METHODS: A cross-sectional study was conducted amongst pregnant women attending their first ANC visit in rural Capricorn District and peri-urban Tlokwe sub-district communities in South Africa. Data collection included questionnaires and medical record abstraction. Bivariate and multivariate analyses assessed factors associated with late ANC presentation. RESULTS: We recruited 807 pregnant women. Of these, 51% of rural women and 28% of peri-urban women presented late for first ANC. Rural women were more likely to present late for first ANC (AOR = 2.65; 95% CI 1.98-3.55) and report barriers to accessing ANC services (P<0.0001). Late ANC presentation in rural communities was associated with being married (AOR = 2.36; 95% CI 1.33-4.19), employed (AOR = 1.90; 95% CI 1.03-3.50), <20 years of age (AOR = 2.19; 95% CI 1.10-4.37), and reporting an unplanned pregnancy (AOR = 2.21; 95% CI 1.40-3.50). Late presentation in peri-urban communities was associated with unplanned pregnancy (AOR = 1.67; 95% CI 1.01-2.74), being told to come back later to initiate ANC after presenting early (AOR 0.51; 95% CI 0.30-0.89) and being pregnant for the first time (AOR = 0.56; 95% CI 0.34-0.94). CONCLUSION: Both rural and peri-urban women had high rates of late presentation for first ANC. However, women in the rural communities were more likely to present late. Unplanned pregnancy was an independent risk factor in both rural and peri-urban communities. Interventions around family planning, especially for adolescent girls and young women, are needed to improve early presentation for ANC.

The South African Rea Phela Health Study: A randomized controlled trial of communication retention strategies.

Epidemiological transitions are occurring throughout Africa. To inform public health programs and policies, longitudinal cohorts investigating non-communicable diseases are needed. However, loss-to-follow up is a major problem. In preparation for a longitudinal study, we conducted a randomized controlled trial to test communication-based retention strategies (message content and delivery methods) among a pilot cohort of South African healthcare workers (n = 1536; median age = 36; women = 1270). Two messaging formats across three delivery modes were tested. Response rates were analyzed by intervention, survey return date and method using chi-square tests and univariate logistic regression. Sixty-seven of 238 (17.4%) control group participants and 238 of 1152 (24.6%) intervention group participants were retained (OR 1.54: CI 1.15-2.07; P = 0.004). Odds of being retained were 1.68 times greater for participants who received regular contact and themed messages compared to control (CI 1.22-2.32; P = 0.001). Neither health status nor clinical condition affected response rates (P>0.05). Time-to-first contact did not impact response rates (P>0.05). Message content and delivery method influenced response rates compared to the control, however no difference was found between intervention groups. Although greater retention is required for valid cohort studies, these findings are the first to quantitatively assess retention factors in Africa.

Efficient mucosal transmissibility but limited pathogenicity of R5 SHIV SF162P3N in Chinese-origin rhesus macaques.

BACKGROUND: Infection of rhesus macaques (RMs) of Indian origin with simian immunodeficiency virus or simian-HIV (SHIV) provided powerful tools to study HIV-1 transmission and disease and for testing the efficacy of novel drugs, vaccines, and prevention strategies. In developing alternative nonhuman primate AIDS models for the CCR5 (R5)-tropic SHIVSF162P3N, we characterized virus transmission and infection in Chinese-origin RMs. METHODS: Virologic, immunologic, and pathogenic evaluations of R5 SHIVSF162P3N infection in Chinese RMs challenged intrarectally (ir) or intravaginally were performed and compared with those previously observed in Indian-origin rhesus exposed to the same inoculum dose and via similar route. RESULTS: R5 SHIVSF162P3N transmits efficiently across mucosal surfaces in Chinese RMs. The magnitude and kinetics of early virus dissemination after ir inoculation in the Chinese macaques were similar to those observed in Indian rhesus, but a trend toward increased SHIVSF162P3N vaginal infectivity and rapid virus spread was seen in the Chinese macaques compared with the Indian-origin animals. Once infected, however, set point viremia in the ir- and intravaginal-infected Chinese rhesus was significantly lower and the animals survived longer compared with infected Indian rhesus. CONCLUSIONS: The R5 SHIVSF162P3N/Chinese RM infection model is suitable for studies of mucosal HIV-1 transmission and protection, but the high frequency of spontaneous control of chronic viremia and reduced virulence with SHIVSF162P3N in this macaque subspecies may limit its utility in studying HIV-1 pathogenesis and in evaluating vaccines and antiretrovirals that rely on reduction in chronic viral load or AIDS development as an experimental end point.