'If you are found taking medicine, you will be called names and considered less of a man': young men's engagement with HIV treatment and care during ulwaluko (traditional initiation and circumcision) in the Eastern Cape Province of South Africa.

This paper explores how HIV-positive abakhwetha (young male initiates) undergoing ulwaluko (traditional Xhosa initiation and circumcision) engage with HIV-related biomedical care and treatment. Health-focused life history narratives (n = 36), semi-structured interviews (n = 32) and analysis of health facility files (n = 41) with adolescent boys and young men (ages 13-24) living with HIV, and semi-structured interviews with traditional and biomedical health practitioners (n = 14) were conducted in 2017 and 2018. This research was part of the Mzantsi Wakho study, a longitudinal, mixed methods study of adolescents living with HIV (n = 1060). Findings demonstrate that ulwaluko rules of not engaging with biomedical care and treatment pose a challenge for initiates who are taking chronic medicine. Fears of inadvertent disclosure of their HIV-positive status collide with the pressure to successfully complete ulwaluko in order to be legitimised as men. In response to this dilemma, they engage a variety of strategies - including taking medicine in secret by hiding them, having a trusted person deliver them discretely, and stopping medicine-taking altogether. The three months following ulwaluko also pose a challenge in accessing biomedical treatment and care. In this time of high surveillance, amakrwala (new men) do not present at health facilities for fear of being thought to have had a botched circumcision or to have contravened 'manhood rules' and left ulwaluko before having healed properly. To get around this, those who continued taking medicine engaged caregiver pick-ups. Beyond suggesting that ulwaluko is a high-risk time for disengagement from biomedical treatment and care, this paper builds on a robust scholarship on the importance of locality and context in gender and health research. It documents the creativity, agency and resilience of initiates and their families as they subvert and re-signify health-related masculine norms.

How front-line healthcare workers respond to stock-outs of essential medicines in the Eastern Cape Province of South Africa.

Shortages of essential medicines are a daily occurrence in many of South Africa (SA)'s public health facilities. This study focuses on the responses of healthcare workers to stock-outs, investigating how actors at the 'front line' of public health delivery understand, experience and respond to shortages of essential medicines and equipment in their facilities. Findings are based on focus groups, observations and interviews with healthcare workers and patients at healthcare facilities in the Eastern Cape Province of SA, conducted as part of the Mzantsi Wakho study. The research revealed a discrepancy between 'informal' definitions of stock-outs and their reporting through formal stock-out management channels. Front-line healthcare workers had designed their own systems for classifying the severity of stock-outs, based on the product in question, and on their potential to access stocks from other facilities. Beyond formal systems of procurement and supply, healthcare workers had established vast networks of alternative communication and action, often using personal resources to procure medical supplies. Stock-outs were only reported when informal methods of stock-sharing did not secure top-up supplies. These findings have implications for understanding the frequency and severity of stock-outs, and for taking action to prevent and manage stock-outs effectively.

Achieving equity in HIV-treatment outcomes: can social protection improve adolescent ART-adherence in South Africa?

Low ART-adherence amongst adolescents is associated with morbidity, mortality and onward HIV transmission. Reviews find no effective adolescent adherence-promoting interventions. Social protection has demonstrated benefits for adolescents, and could potentially improve ART-adherence. This study examines associations of 10 social protection provisions with adherence in a large community-based sample of HIV-positive adolescents. All 10-19-year-olds ever ART-initiated in 53 government healthcare facilities in a health district of South Africa's Eastern Cape were traced and interviewed in 2014-2015 (n = 1175 eligible). About 90% of the eligible sample was included (n = 1059). Social protection provisions were "cash/cash in kind": government cash transfers, food security, school fees/materials, school feeding, clothing; and "care": HIV support group, sports groups, choir/art groups, positive parenting and parental supervision/monitoring. Analyses used multivariate regression, interaction and marginal effects models in SPSS and STATA, controlling for socio-demographic, HIV and healthcare-related covariates. Findings showed 36% self-reported past-week ART non-adherence (<95%). Non-adherence was associated with increased opportunistic infections (p = .005, B .269, SD .09), and increased likelihood of detectable viral load at last test (>75 copies/ml) (aOR 1.98, CI 1.1-3.45). Independent of covariates, three social protection provisions were associated with reduced non-adherence: food provision (aOR .57, CI .42-.76, p < .001); HIV support group attendance (aOR .60, CI .40-.91, p < .02), and high parental/caregiver supervision (aOR .56, CI .43-.73, p < .001). Combination social protection showed additive benefits. With no social protection, non-adherence was 54%, with any one protection 39-41%, with any two social protections, 27-28% and with all three social protections, 18%. These results demonstrate that social protection provisions, particularly combinations of "cash plus care", may improve adolescent adherence. Through this they have potential to improve survival and wellbeing, to prevent HIV transmission, and to advance treatment equity for HIV-positive adolescents.

From comprehensive medicine to public health at the University of Cape Town: a 40-year journey.

We explore the history of the School of Public Health at the University of Cape Town and its relationship to changes in the understanding of the role of public health both nationally and internationally. We draw from primary and secondary sources to trace the emergence, growth and development of the School, and to situate these processes within the socio-political, clinical and public health contexts in South Africa and internationally.

Cutting edge: telomerase activation in human T lymphocytes does not require increase in telomerase reverse transcriptase (hTERT) protein but is associated with hTERT phosphorylation and nuclear translocation.

Capacity for cellular replication is critically important for lymphocyte function and can be regulated by telomerase-dependent maintenance of telomere length. In contrast to most normal human somatic cells that do not express telomerase due to the failure to transcribe telomerase reverse transcriptase (hTERT), lymphocytes express telomerase in a highly regulated fashion yet constitutively transcribe hTERT during development and activation. Here, we report that hTERT protein is present in both thymocytes and blood T cells at equivalent levels despite their substantial differences in telomerase activity, and that induction of telomerase activity in resting CD4(+) T cells is not dependent on net hTERT protein increase. Moreover, hTERT is phosphorylated and translocated from cytoplasm to nucleus during CD4(+) T cell activation. Thus, human T lymphocytes regulate telomerase function through novel events independent of hTERT protein levels, and hTERT phosphorylation and nuclear translocation may play a role in regulation of telomerase function in lymphocytes.

Mouse endogenous superantigens: Ms and Mls-like determinants encoded by mouse retroviruses.

Commonly used inbred mouse strains express different combinations of integrated mouse mammary tumor proviruses (MMTV). This appendix summarizes the proviruses that have been detected. The reported functional properties of those MMTV proviral products which have been identified as superantigens are also summarized, including the ability to elicit primary or secondary T cell responses and to induce Vb-specific clonal deletion during T cell differentiation. In addition, the amino acid sequences of putative ORF gene products of different MMTV are compared.

The role of telomerase expression and telomere length maintenance in human and mouse.

The molecular regulation of telomere length has been well elucidated by a series of elegant studies over the past decade. More recently, experimental evidence has accrued that addresses the challenging question of if and how telomere length regulation may contribute to normal human aging or to human disease. Recent studies in mice have provided a mammalian precedent indicating that telomerase deficiency can lead to in vivo dysfunction, most probably as a consequence of progressive telomere shortening. In humans, the evidence that telomere shortening might lead to in vivo dysfunction is far less direct, although the recent description of telomerase deficiency and telomere shortening associated with the DKC syndrome is suggestive of such a link. Methodologies exist and continue to be developed that are increasingly capable of manipulating telomerase activity and telomere length in human cells. It remains to be determined whether scientifically rigorous and (equally important) medically ethical approaches will emerge to directly assess the ability of telomere length modulation to correct functional disorders of human cellular function ex vivo or more challenging still, in vivo.

Lineage-specific telomere shortening and unaltered capacity for telomerase expression in human T and B lymphocytes with age.

Age effects on telomere length and telomerase expression in peripheral blood lymphocytes were analyzed from 121 normal individuals age newborn to 94 years and revealed several new findings. 1) Telomere shortening was observed in CD4+ and CD8+ T and B cells with age. However, the rate of telomere loss was significantly different in these populations, 35 +/- 8, 26 +/- 7, and 19 +/- 7 bp/year for CD4+ and CD8+ T and B cells, respectively. In addition, CD4+ T cells had the longest average telomeres at all ages, followed by B cells, with CD8+ T cell telomeres the shortest, suggesting that these lymphocyte populations may have different replicative histories in vivo. 2) Telomerase activity in freshly isolated T and B cells was indistinguishably low to undetectable at all ages but was markedly increased after Ag and costimulatory receptors mediated stimulation in vitro. Furthermore, age did not alter the magnitude of telomerase activity induced after stimulation of T or B lymphocytes through Ag and costimulatory receptors or in response to PMA plus ionomycin treatment. 3) The levels of telomerase activity induced by in vitro stimulation varied among individual donors but were highly correlated with the outcome of telomere length change in CD4+ T cells after Ag receptor-mediated activation. Together, these results indicate that rates of age-associated loss of telomere length in vivo in peripheral blood lymphocytes is specific to T and B cell subsets and that age does not significantly alter the capacity for telomerase induction in lymphocytes.

Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice.

The majority of Atm-deficient mice die of malignant thymic lymphoma by 4-5 mo of age. Cytogenetic abnormalities in these tumors are consistently identified within the Tcr alpha/delta locus, suggesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA breaks that occur during V(D)J recombination. Since V(D)J recombination is a recombinase-activating gene (RAG)-dependent process, we generated Rag2(-/-)Atm(-/-) mice to assess the requirement for RAG-dependent recombination in thymic lymphomagenesis. In contrast to expectation, the data presented here indicate that development of malignant thymic lymphoma in Atm(-/-) mice is not prevented by loss of RAG-2 and thus is not dependent on V(D)J recombination. Malignant thymic lymphomas in Rag2(-/-)Atm(-/-) mice occurred at a lower frequency and with a longer latency as compared with Atm(-/-) mice. Importantly, cytogenetic analysis of these tumors indicated that multiple chromosomal abnormalities occurred in each tumor, but that none of these involved the Tcr alpha/delta locus. Nonmalignant peripheral T cells from TCR-transgenic Rag2(-/-)Atm(-/-) mice also revealed a substantial increase in translocation frequency, suggesting that these translocations are early events in the process of tumorigenesis. These data are consistent with the hypothesis that the major mechanism of tumorigenesis in Atm(-/-) mice is via chromosomal translocations and other abnormalities that are secondary to aberrant responses to double-stranded DNA breaks. Furthermore, these data suggest that V(D)J recombination is a critical, but not essential, event during which Atm-deficient thymocytes are susceptible to developing chromosome aberrations that predispose to malignant transformation.

The role of B7 costimulation in CD4/CD8 T cell homeostasis.

The effect of B7-mediated costimulation on T cell homeostasis was examined in studies of B7-1 (CD80) and B7-2 (CD86) transgenic as well as B7-deficient mice. B7 overexpression in transgenic mice resulted in marked polyclonal peripheral T cell hyperplasia accompanied by skewing toward an increased proportion of CD8 single-positive cells and a decreased proportion of CD4 single-positive cells in thymus and more markedly in peripheral T cells. B7-induced T cell expansion was dependent on both CD28 and TCR expression. Transgenic overexpression of B7-1 or B7-2 resulted in down-regulation of cell surface CD28 on thymocytes and peripheral T cells through a mechanism mediated by intercellular interaction. Mice deficient in B7-1 and B7-2 exhibited changes that were the reciprocal of those observed in B7-overexpressing transgenics: a marked increase in the CD4/CD8 ratio in peripheral T cells and an increase in cell surface CD28 in thymus and peripheral T cells. These reciprocal effects of genetically engineered increase or decrease in B7 expression indicate that B7 costimulation plays a physiological role in the regulation of CD4+ and CD8+ T cell homeostasis.

Constitutive and regulated expression of telomerase reverse transcriptase (hTERT) in human lymphocytes.

Human telomerase consists of two essential components, telomerase RNA template (hTER) and telomerase reverse transcriptase (hTERT), and functions to synthesize telomere repeats that serve to protect the integrity of chromosomes and to prolong the replicative life span of cells. Telomerase activity is expressed selectively in germ-line and malignant tumor cells but not in most normal human somatic cells. As a notable exception, telomerase is expressed in human lymphocytes during development, differentiation, and activation. Recent studies have suggested that regulation of telomerase is determined by transcription of hTERT but not hTER. The highly regulated expression of telomerase in lymphocytes provides an opportunity to analyze the contribution of transcriptional regulation of hTERT and hTER. We report here an analysis of hTERT expression by Northern and in situ hybridization. It was found that hTERT mRNA is expressed at detectable levels in all subsets of human lymphocytes isolated from thymus, tonsil, and peripheral blood, regardless of the status of telomerase activity. hTERT expression is regulated as a function of lineage development, differentiation, and activation. Strikingly, however, telomerase activity in these cells is not correlated strictly with the levels of hTERT and hTER transcripts. The absence of correlation between telomerase activity and hTERT mRNA could not be attributed to the presence of hTERT splice variants or to detectable inhibitors of telomerase activity. Thus, transcriptional regulation of hTERT is not sufficient to account for telomerase activity in human lymphocytes, indicating a likely role of posttranscriptional factors in the control of enzyme function.

The role of B7-CD28 co-stimulation in tumor rejection.

The role of B7 co-stimulatory signaling in in vivo tumor rejection remains incompletely characterized. In particular, the relative competence of B7-1 (CD80) and B7-2 (CD86) to provide effective co-stimulus is not well defined, and the identification of the T cell co-stimulatory receptor that mediates B7 co-stimulation in tumor rejection has not been addressed. These issues were studied by assessing rejection of B7-negative or B7-transfected tumor cells in CD28-expressing or CD28-deficient hosts. B7-negative EL4 tumor cells grew progressively in normal syngeneic C57BUL6 (B6) mice. In contrast EL4 cells transfected with either full length B7-1 or full length B7-2 were rejected, indicating that both B7-1 and B7-2 are competent to mediate rejection of EL4 tumor cells. Expression of truncated B7-1 or B7-2 products, with complete deletion of cytoplasmic domains, was as effective as expression of full length B7-1 or B7-2 in mediating rejection. In contrast to the rejection of B7-transfected EL4 cells observed in CD28-expressing syngeneic hosts, B7-1- and B7-2-positive EL4 cells as well as control EL4 cells grew progressively in CD28-deficient mice, demonstrating the requirement for host expression of CD28 in B7-mediated tumor rejection. These results indicate that interaction of host CD28 with co-stimulatory extracellular B7-1 or B7-2 ligands expressed on tumor cells can play a necessary role in mediating tumor rejection.

Telomere length regulation in mice is linked to a novel chromosome locus.

Little is known about the mechanisms that regulate species-specific telomere length, particularly in mammalian species. The genetic regulation of telomere length was therefore investigated by using two inter-fertile species of mice, which differ in their telomere length. Mus musculus (telomere length >25 kb) and Mus spretus (telomere length 5-15 kb) were used to generate F1 crosses and reciprocal backcrosses, which were then analyzed for regulation of telomere length. This analysis indicated that a dominant and trans-acting mechanism exists capable of extensive elongation of telomeres in somatic cells after fusion of parental germline cells with discrepant telomere lengths. A genome wide screen of interspecific crosses, using M. spretus as the recurrent parent, identified a 5-centimorgan region on distal chromosome 2 that predominantly controls the observed species-specific telomere length regulation. This locus is distinct from candidate genes encoding known telomere-binding proteins or telomerase components. These results demonstrate that an unidentified gene(s) mapped to distal chromosome 2 regulates telomere length in the mouse.

Cutting edge: antigen-dependent regulation of telomerase activity in murine T cells.

Telomeres, structures on the ends of linear chromosomes, function to maintain chromosomal integrity. Telomere shortening occurs with cell division and provides a mechanism for limiting the replicative potential of normal human somatic cells. Telomerase, a ribonucleoprotein enzyme, synthesizes telomeric repeats on chromosomal termini, potentially extending the capacity for cell division. The present study demonstrates that resting T cells express little/no activity, and optimal Ag-specific induction of telomerase activity in vitro requires both TCR and CD28-B7 costimulatory signals. Regulation of telomerase in T cells during in vivo Ag-dependent activation was also assessed by adoptive transfer of TCR transgenic T cells and subsequent Ag challenge. Under these conditions, telomerase was induced in transgenic T cells coincident with a phase of extensive clonal expansion. These findings suggest that telomerase may represent an adoptive response that functions to preserve replicative potential in Ag-reactive lymphocytes.

Productive infection of neonatal CD8+ T lymphocytes by HIV-1.

CD8+ T lymphocytes confer significant but ultimately insufficient protection against HIV infection. Here we report that activated neonatal CD8+ T cells can be productively infected in vitro by macrophage-tropic (M-tropic) HIV-1 isolates, which are responsible for disease transmission, whereas they are resistant to T cell-tropic (T-tropic) HIV strains. Physiological activation of CD8-alpha/beta+ CD4- T cell receptor-alpha/beta+ neonatal T cells, including activation by allogeneic dendritic cells, induces the accumulation of CD4 messenger RNA and the expression of CD4 Ag on the cell surface. The large majority of anti-CD3/B7.1-activated cord blood CD8+ T cells coexpress CD4, the primary HIV receptor, as well as CCR5 and CXCR4, the coreceptors used by M- and T-tropic HIV-1 strains, respectively, to enter target cells. These findings are relevant to the rapid progression of neonatal HIV infection. Infection of primary HIV-specific CD8+ T cells may compromise their survival and thus significantly contribute to the failure of the immune system to control the infection. Furthermore, these results indicate a previously unsuspected level of plasticity in the neonatal immune system in the regulation of CD4 expression by costimulation.