Effects of systemic biomarkers on HIV-1 acquisition and subtype A and C infections Public

McInally, Samantha (Summer 2021)

Permanent URL: https://etd.library.emory.edu/concern/etds/cj82k843z?locale=fr
Published

Abstract

Despite the wealth of knowledge gathered since its discovery in the 1980s, HIV-1 remains one of the greatest health crisis’s facing the world today. In particular, sub- Saharan African bears almost two-thirds of the global disease burden. Within this region, the most common subtypes of HIV-1 seen are subtype A and C. While the geographical distribution and clinical disease progression of different subtypes in Africa is known, there is less known about the immunological baseline state of the individuals living in this high-risk region. One way to study this is by examining the levels of biomarkers, cytokines and chemokines, in these individuals. Levels of biomarkers can help identify different stages of HIV infection, the presence of other infections/diseases, and help us further understand the effect that HIV-1 has on the innate immune response.

In the first study presented in this dissertation, we studied biomarker levels in two groups of individuals in serodiscordant couples from sub-Saharan Africa: uninfected individuals that remained HIV-negative and uninfected individuals that would finally seroconvert and become HIV-positive. Through our analysis, we found that individuals that eventually became HIV-positive had significantly higher levels of multiple biomarkers compared to individuals that remained HIV-negative. In addition, we were able to identify several biomarkers that could predict individuals who would become HIV-positive; the ones identified were non-classical inflammatory biomarkers and suggests that other infections or chronic diseases may increase an individuals’ risk for HIV acquisition.

In the second study presented in this dissertation, we investigated the basis for the higher viral loads and faster CD4 loss seen in subtype C vs subtype A infected individuals. We showed that the replicative capacity of the transmitted founder viruses from HIV-1 subtype A and C infections were similar and therefore was unlikely to differentially impact disease progression. While levels of the biomarkers during acute infection were similar between the two subtypes, we noticed that there was a higher number of biomarkers whose levels significantly increased from their pre-infection levels with subtype C compared to subtype A infections. This shows that the clinical differences observed during infection by these two subtypes is not reflected in biomarker levels during acute infection and therefore islikely is linked to the adaptive immune response. Clearly this is a complicated question that is still unanswered.

The use of biomarkers helped show the increased risk of individuals with elevated biomarkers for HIV acquisition and showed subtle differences in the biomarker response between HIV-1 subtype A and C acute infections. Biomarker studies can help reveal additional information about all phases of HIV-1 infections. 

Table of Contents

Tables of Contents Chapter I

Introduction................................................................................................11 Figures......................................................................................................36

Fig 1. Differences in clinical disease progression in HIV-1 subtype A, C, and D infections...................................................................................36

Fig 2. Selection Bottleneck in HIV-1 genital transmission.....................37

Fig 3. Consensus bias exists for HIV-1 subtype C transmission............38 References.................................................................................................39 Chapter II: Elevated levels of inflammatory plasma biomarkers are associated with risk of HIV infection..............................................................................50 Figures......................................................................................................72

Fig. 1. Circulating biomarkers in the combined Rwanda and Zambia cohorts: preinfection individuals have significantly higher cytokines and chemokine levels compared to the uninfected group.....................................................................72

Fig. 2. Partial least square (PLS) and Random Forest Analysis supported initial analyses......................................................................................................73 Fig. 3. Preinfection individuals have significantly higher cytokines and chemokine

levels compared to the uninfected group when individuals exhibiting genital inflammation/ulceration are excluded.................................................................74 Fig. 4. Circulating biomarkers in the Rwanda cohort: preinfection individuals have

significantly higher cytokines and chemokine levels compared to the uninfected group..........................................................................................................75

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Fig. 5. Circulating biomarkers in the Zambia cohort: preinfection individuals have significantly higher cytokines and chemokine levels compared to the uninfected group..........................................................................................................76

Fig. 6. Receiver Operating Characteristics (ROC) curves for combined Zambia and Rwanda cohorts identifies biomarkers that distinguishes preinfection individuals...................................................................................................77

Fig. 7. Kfold validation model identifies elevated ITAC and IL-7 levels as markers for preinfection from combined Rwandan and Zambian cohorts..............................78 Supplemental Materials................................................................................79 References.................................................................................................90 Chapter III: Comparison of viral phenotype and inflammatory biomarker responses in HIV-1 acute subtype A and C infections............................................................100 Figures.....................................................................................................120

Tab. 1. Demographics of the cohorts used in experiments in this paper.........120

Fig. 1. Comparison of viral phenotypes during acute infection of HIV-1 subtype A and C transmitted-founder (TF) viruses............................................................121

Fig. 2. In vitro replication capacity of full-length TF IMCs predicts CD4 loss and inflammatory cytokine profiles........................................................................122

Fig. 3. More biomarkers are significantly increased post infection in HIV-1 C compared to subtype A.................................................................................124

Fig. 4. Partial Least Square (PLS) analysis of changing biomarker profiles pre and post infection in HIV-1 subtype C and A acute infection cohort........................125

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Fig. 5. ITAC is a biomarker associated with HIV pathogenesis and higher vRC..........................................................................................................126 References................................................................................................128 Chapter IV: Discussion...............................................................................135 Figures.....................................................................................................148

Fig. 1. ITAC regulates chemotaxis to sites of infection or injury.....................148

Fig. 2. Binding of ITAC to CXCR3 on CD4+ T cell upregulate surface expression of CCR5....................................................................................................149 References................................................................................................150 Appendix..................................................................................................164 Appendix A: Isolation of genetic sequences of 10 subtype A and 10 subtype C transmission pairs.......................................................................................165 Figures.....................................................................................................169

Fig. 1. Phylogenetic analysis of 10 subtype A transmission pairs..................169

Fig. 2. Nucleotide sequence of full-length subtype A transmitted-founder viruses are not closer to the subtype A cohort consensus compared to the sequences of non- transmitted donor viruses..............................................................................170

Fig. 3. Amino acid sequences of HIV-1 genes of subtype A transmitted-founder viruses are not closer to the subtype A cohort consensus compared to the sequences of non-transmitted donor viruses for viral genes (A) gag, (B) pol, (C) env, (D) nef.........171

Fig. 4. Phylogenetic analysis of 10 subtype C transmission pairs. Sequence of the transmitted-founder virus is shown with a red dot, while the rest of the branches are the non-transmitted donor viral sequences........................................................172

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Fig. 5. Nucleotide sequence of full-length subtype C transmitted-founder viruses are closer to the subtype C consensus sequence compared to the sequences of nontransmitted donor viruses.........................................................................173

Fig. 6. Amino acid sequences of HIV-1 genes gag, env, and enf of subtype C transmitted-founder viruses are closer not to the subtype C consensus compared to the sequences of nontransmitted donor viruses......................................................174 Appendix B: Generation of infectious molecular clones for seven new transmission pairs.....................................................................................175 Figures.....................................................................................................177

Fig. 1. Titers of newly generated subtype A and C transmission pairs............177 References................................................................................................178 

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