Introduction: This study is a secondary data analysis of HIV/AIDS patients on Anti-retroviral Therapy (ART), at Themba Lethu HIV/AIDS clinic, who have had the first break in the continuity of taking their Antiretrovirals (ARVs) of more than 10 days, measured by patient missing the refill appointment for more than 10 days. The clinic started in 2004. HIV/AIDS is high in South Africa with about 400,000 AIDS patients on ARVs. For ARVs to be most effective they must be taken continuously without breaks, and for life. Without this, there is risk of ARVS drug resistance development and consequent failure of the ART program. Some patients may break this continuity and this seems to be a problem in South Africa. Where the patients develops side-effects or is not responding well to treatment, clinicians may also cause a break in the therapy. This study described the first break as when it occurred and for how long it lasted, investigated the factors associated with this break and the association of the first break and the last CD4 count. Materials and methods: 7,930 adults (≥18 years, either gender) on ART and baseline CD4 <250 cells/μl were included in the study. The study group were patients who had first break in continuity of therapy of more than 10 days. The first break was described as when it occurred after months of ART initiation and how long(days) the first break lasted. Patients on Post- Exposure Prophylaxis, single-dose Nevirapine, Prevention-of mother-To-Child- transmission therapy, and those with breaks in therapy of more than 364 days were excluded. Outcome variables was the last CD4 count. Analyses were in STATA 10, at 95% confidence interval. Median and quartile ranges were used to describe participants in the study. T-test, Fishers exact test and chi-square were used to compare groups. Regression was used to determine demographic and clinical factors associated with first break in therapy and also to determine the association of first break in therapy and the last CD4 count. Results: The median duration on ART for the patients was 764 days. 63% of patients had a break in ART. 47.5% of patients had their first break in therapy within the first 2 years of being on the ART program, with the largest proportion within the first 6 months of therapy. Most patient came with advanced disease(CD4 <100cells/μl, WHO clinical staging IV). Women were twice more than men. They tended to come earlier for therapy, took longer to improve and delayed in having the first break compared to men (254 vs. 205 days). Baseline hemoglobin and unemployment were factors associated with when the first break occurred. The median length of first break was 21 (Q1-Q3 7-43) Unemployment and baseline hemoglobin were associated with length of first break. The first break in therapy was associated with the last CD4 count. The longer the patient stayed on ART without the first break, the higher the last CD4 would be. Peripheral neuropathy had a statistically significant positive association with the last CD4 count. However, baseline CD4, Age, baseline BMI, WHO stage IV, baseline hemoglobin and unemployment had a statistically significant but negative association with the last CD4 count. The weakness of using the missing appointment system is that it does not inform clinician whether patients is really taking or not taking ARVs at home. Its strength over the self reported adherence system is that it is free of recall bias. Conclusion: Though Themba Lethu clinic has a follow-up system in place for patients missing refill appointment, up to 63% patient missed their appointment to collect medicine on time and this had a negative effect on the last CD4. There is need to strengthen existing follow-up method besides decentralising the ART services in Johannesburg.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg 2014 / Human receptor CD4 is a membrane-bound glycoprotein expressed on the surface of certain leukocytes where it plays a key role in the activation of immunostimulatory T cells. This function is diverted by the Human Immunodeficiency Virus (HIV) envelope glycoprotein (gp120), which uses CD4 as its primary receptor for cell entry. The requirement of CD4 for viral entry has rationalised the development of recombinant CD4-based proteins as competitive viral attachment inhibitors and immunotherapeutic agents. While growing evidence suggests that redox exchange reactions involving CD4 disulphides (potentially catalysed by cell surface-secreted oxidoreductases) play an essential role in regulating the activity of CD4, their mechanism(s), biological utility and structural consequences that may be applicable to the designs of novel antiviral therapies and vaccines remain incompletely understood. Herein, a novel recombinant CD4 protein designed to bind gp120 through a targeted disulphide-exchange mechanism is described. This molecule contains a conservative Ser60 to Cys mutation on the CD4 domain 1 α-helix which, according to theoretical crystal structure modelling, positions a thiol in close proximity of the gp120 V1/V2 loop disulphide (126Cys–Cys196) resulting in the formation of an interchain disulphide bond. Experimental evidence for this effect is provided by describing the expression, purification, refolding, receptor binding and antiviral activity analysis of a recombinant two-domain CD4 variant containing the S60C mutation (2dCD4-S60C). This 2dCD4-S60C binds HIV-1 gp120 with a significantly higher affinity than wild-type protein under conditions that facilitate disulphide exchange and this translates into a corresponding increase in the efficacy of CD4-mediated viral entry inhibition. To gain more insights into the importance of redox activity in the mechanism of HIV entry, a panel of recombinant 2-domain CD4 proteins (2dCD4), including wild-type and Cys/Ala variants, were used to show that Thioredoxin (Trx), an oxidoreductase found on the cell surface, reduces 2dCD4 highly efficiently, catalysing the formation of conformationally distinct monomeric 2dCD4 isomers, and a stable, disulphide-linked 2dCD4 dimer. HIV-1 gp120 was shown to be incapable of binding a fully oxidised, monomeric 2dCD4 in which both domain 1 and 2 disulphides are intact, but binds robustly to reduced equivalents that are the products of Trx-mediated isomerisation. This Trx-driven dimerisation of CD4, a process believed to be critical for the establishment of functional MHCII-TCR-CD4 antigen presentation complexes, is shown to be impaired when CD4 is bound to gp120. Finally, preliminary, low-resolution structural analysis of individual CD4 domains 1 and 2 are suggestive of intrinsic metastability in domain 2, and reduction of its resident allosteric disulphide bond likely underpins the structural rearrangements in CD4 that are required for efficient interaction with gp120. Overall, these findings emphasise the fundamental importance of redox pathways in the biochemical mechanism of HIV entry, and illustrate the feasibility of exploiting these for the development of novel antiviral ligands.

Thesis (Ph. D.)--Cornell University, 1989. / Vita. Includes bibliographical references.

Naturally-occurring CD4+Foxp3+ regulatory T cells (nTreg) play a central role in maintaining immune self-tolerance as well as modulating immunity towards pathogens. Pathogens may establish chronic infections in immunocompetent hosts by engaging nT reg in order to promote immunosuppression. The goal of the research described here is to test the hypothesis that nTreg modulate protective immunity to malaria, and consequentially affect susceptibility to the parasite. To investigate this question, the functional dynamics of CD4+Foxp3 + nTreg cells were evaluated in mice infected with blood-stage Plasmodium chabaudi AS. Adoptive transfer of nTreg to infected wild-type C57BL/6 (B6) mice or infection of transgenic B6 mice over-expressing Foxp3 resulted in increased parasitemia and reduced survival compared to control mice. Moreover, while resistant B6 mice exhibited decreased splenic nT reg frequencies at day 7 post infection, susceptible A/J mice maintained high numbers of nTreg at this time. Investigation of the effects of nTreg regulation on immune cell function in P. chabaudi AS-infected mice revealed that increased nTreg frequencies led to decreased malaria-specific lymphoproliferation and increased systemic levels of IL-10. Unlike B6 mice, increased splenic nTreg frequencies in infected A/J mice correlated with decreased effector T cell proliferation and IFN-gamma secretion, decreased B cell and NK cell proliferation as well as deficient IFN-gamma secretion by NK cells. Finally, nTreg proliferated within infected sites in both B6 and A/J mice, albeit to a greater extent in susceptible A/J mice. Altogether, these results demonstrate that nTreg suppressed anti-malarial immunity, and in turn promoted parasite growth and persistence.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Thesis (Ph. D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Vita. Bibliography: 152-170.

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references (leaves [115]-128).

Thesis (Ph. D.)--Cornell University, May, 2007. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Virginia, 2007. / Includes bibliographical references. Also available online through Digital Dissertations.

No description available.