New findings on the dynamics of HIV and TB coinfection models

In this paper we study a model for HIV and TB coinfection. We consider the integer order and the fractional order versions of the model. Let α∈[0.78,1.0] be the order of the fractional derivative, then the integer order model is obtained for α=1.0. The model includes vertical transmission for HIV and treatment for both diseases. We compute the reproduction number of the integer order model and HIV and TB submodels, and the stability of the disease free equilibrium. We sketch the bifurcation diagrams of the integer order model, for variation of the average number of sexual partners per person and per unit time, and the tuberculosis transmission rate. We analyze numerical results of the fractional order model for different values of α, including α=1. The results show distinct types of transients, for variation of α. Moreover, we speculate, from observation of the numerical results, that the order of the fractional derivative may behave as a bifurcation parameter for the model. We conclude that the dynamics of the integer and the fractional order versions of the model are very rich and that together these versions may provide a better understanding of the dynamics of HIV and TB coinfection

Integrating Community-Based Interventions to Reverse the Convergent TB/HIV Epidemics in Rural South Africa.

The WHO recommends integrating interventions to address the devastating TB/HIV co-epidemics in South Africa, yet integration has been poorly implemented and TB/HIV control efforts need strengthening. Identifying infected individuals is particularly difficult in rural settings. We used mathematical modeling to predict the impact of community-based, integrated TB/HIV case finding and additional control strategies on South Africa's TB/HIV epidemics. We developed a model incorporating TB and HIV transmission to evaluate the effectiveness of integrating TB and HIV interventions in rural South Africa over 10 years. We modeled the impact of a novel screening program that integrates case finding for TB and HIV in the community, comparing it to status quo and recommended TB/HIV control strategies, including GeneXpert, MDR-TB treatment decentralization, improved first-line TB treatment cure rate, isoniazid preventive therapy, and expanded ART. Combining recommended interventions averted 27% of expected TB cases (95% CI 18-40%) 18% HIV (95% CI 13-24%), 60% MDR-TB (95% CI 34-83%), 69% XDR-TB (95% CI 34-90%), and 16% TB/HIV deaths (95% CI 12-29). Supplementing these interventions with annual community-based TB/HIV case finding averted a further 17% of TB cases (44% total; 95% CI 31-56%), 5% HIV (23% total; 95% CI 17-29%), 8% MDR-TB (68% total; 95% CI 40-88%), 4% XDR-TB (73% total; 95% CI 38-91%), and 8% TB/HIV deaths (24% total; 95% CI 16-39%). In addition to increasing screening frequency, we found that improving TB symptom questionnaire sensitivity, second-line TB treatment delays, default before initiating TB treatment or ART, and second-line TB drug efficacy were significantly associated with even greater reductions in TB and HIV cases. TB/HIV epidemics in South Africa were most effectively curtailed by simultaneously implementing interventions that integrated community-based TB/HIV control strategies and targeted drug-resistant TB. Strengthening existing TB and HIV treatment programs is needed to further reduce disease incidence

Modelling coinfection dynamics ofHIVAIDS, tuberculosis and Hepatitis C virus

HIV and coinfection (i.e. Tuberculosis and Hepatitis C) adversely affects the lives of individuals in both the biological and psychosocial aspects. This study focuses on modelling coinfection dynamics of HIV&AIDS and some selected opportunistic infections, there-by determining their long-run and causal relationship. The study focuses on six (6) states in the North West Geo-Political Region of Nigeria, these states under study includes; Kaduna, Sokoto, Katsina, Kano, Zamfara and Kebbi. The Johansen Multivariate Cointegration approach was applied to establish the long-run relationship among variables and Granger Causality test was also applied to determine whether variables move in either unidirectional or bidirectional. The results for the cointegration test showed that there is a long-run relationship between HIV/AIDS, Tuberculosis and Hepatitis C in Kaduna, Katsina and Kebbi States. While, Granger causality test indicates that, no bidirectional Granger causality is found in the sample period, only unidirectional causality. The test showed that in the short-run HIV/AIDS Granger causes Tuberculosis in Kaduna, Katsina, Zamfara and Kebbi, while, HIV/AIDS Granger causes Hepatitis C in only Kaduna and Sokoto

The Influence of HIV on the Evolution of Mycobacterium tuberculosis.

HIV significantly affects the immunological environment during tuberculosis coinfection, and therefore may influence the selective landscape upon which M. tuberculosis evolves. To test this hypothesis whole genome sequences were determined for 169 South African M. tuberculosis strains from HIV-1 coinfected and uninfected individuals and analyzed using two Bayesian codon-model based selection analysis approaches: FUBAR which was used to detect persistent positive and negative selection (selection respectively favoring and disfavoring nonsynonymous substitutions); and MEDS which was used to detect episodic directional selection specifically favoring nonsynonymous substitutions within HIV-1 infected individuals. Among the 25,251 polymorphic codon sites analyzed, FUBAR revealed that 189-fold more were detectably evolving under persistent negative selection than were evolving under persistent positive selection. Three specific codon sites within the genes celA2b, katG, and cyp138 were identified by MEDS as displaying significant evidence of evolving under directional selection influenced by HIV-1 coinfection. All three genes encode proteins that may indirectly interact with human proteins that, in turn, interact functionally with HIV proteins. Unexpectedly, epitope encoding regions were enriched for sites displaying weak evidence of directional selection influenced by HIV-1. Although the low degree of genetic diversity observed in our M. tuberculosis data set means that these results should be interpreted carefully, the effects of HIV-1 on epitope evolution in M. tuberculosis may have implications for the design of M. tuberculosis vaccines that are intended for use in populations with high HIV-1 infection rates

Doctor of Philosophy

dissertationAround 2-3 billion people worldwide are infected with Mycobacterium tuberculosis (Mtb), the bacteria that causes tuberculosis (TB). Increasing incidence of drug resistant strains of Mtb indicate a growing need for new antibiotics. Pyrrolocins A-C are a set of pyrrolodinediones isolated from an endophytic fungus (NRRL50135) from Papua New Guinea. The mechanism of action for these compounds against Mtb and other bacteria (i.e., Staphylococcus aureus) is largely unknown. We found that pyrrolocins inhibit the first committed step in fatty acid biosynthesis, a mechanism that has yet to be targeted in anti-TB therapy. Current anti-TB drug screening approaches use axenic culture to assess drug efficacy. However this does not assess efficacy against intracellular Mtb infection. In addition, cytotoxicity is determined separately. We developed a screening method in a macrophage cell line that combines infection and cytotoxicity. This screen can be used to determine effects of drug on infected cells as well as uninfected cells. TB is the leading cause of death among HIV/AIDS patients worldwide. Interactions between Mtb and HIV-infected cells have been explored. However these studies have addressed the impact on latent HIV reservoirs. We found that components of the Mtb membrane as well as bacteria co-culture resulted in HIV latency reversal. Macrophages are susceptible to Mtb and HIV infection. We explored concurrent HIV/Mtb infection in vitro. We found a small percentage of our macrophage cell line, and an even smaller percentage of our T cell line, were infected with both HIV and Mtb. Latency reversal and concurrent infection by Mtb in HIV-infected cells identify mechanisms by which Mtb may exacerbate HIV infection. These findings highlight that HIV/Mtb interactions should be considered during anti-HIV and anti-TB drug therapy development as they will likely be implemented in HIV/TB patients. The findings in this work collectively provide new strategies to treat TB and HIV, whether that is offering an alternative to current antibiotics with a novel mechanism, assessing drug efficacy using an in vitro screening method that models intracellular Mtb, or understanding processes (i.e., latency reversal and concurrent infection) that may occur in HIV/TB coinfected patients which could have ultimate consequences on therapeutic efficacy in these patients

Origin of tuberculosis in the Paleolithic predicts unprecedented population growth and female resistance

The project leading to these results has received funding from "la Caixa" Foundation (ID 100010434), under agreement LCF/PR/GN16/10290002Current data estimate the origin of Mycobacterium tuberculosis complex (MtbC) infection around 73,000 years before the common era (BCE), and its evolution to "modern" lineages around 46,000 BCE. Being MtbC a major killer of humanity, the question is how both species could persist. To answer this question, we have developed two new epidemiological models (SEIR type), adapted to sex dimorphism and comparing coinfection and superinfection for different MtbC lineages. We have attributed a higher resistance/tolerance to females to explain the lower incidence noted in this sex, a better health status in the Paleolithic compared to the Neolithic, and a higher dissemination of "modern" lineages compared to "ancient" ones. Our findings show the extraordinary impact caused by "modern" lineages, provoking the extinction of the groups infected. This could only be overcomed by an unprecedented population increase (x20 times in 100 years) and helped with the protection generated by previous infection with "ancient" lineages. Our findings also suggest a key role of female resistance against MtbC. This data obliges us to rethink the growth population parameters in the Paleolithic, which is crucial to understanding the survival of both MtbC and humans, and to decipher the nature of human female resistance against TB

Hidden Consequences of Living in a Wormy World: Nematode-Induced Immune Suppression Facilitates Tuberculosis Invasion in African Buffalo

Most hosts are infected with multiple parasites, and responses of the immune system to co occurring parasites may influence disease spread. Helminth infection can bias the host immune response toward a T-helper type 2 Th2) over a type 1 Th1) response, impairing the host\u27s ability to control concurrent intracellular microparasite infections and potentially modifying disease dynamics. In humans, immune-mediated interactions between helminths and microparasites can alter host susceptibility to diseases such as HIV, tuberculosis TB), and malaria. However, the extent to which similar processes operate in natural animal populations and influence disease spread remains unknown. We used cross-sectional, experimental, and genetic studies to show that gastrointestinal nematode infection alters immunity to intracellular microparasites in free-ranging African buffalo Syncerus caffer). Buffalo that were more resistant to nematode infection had weaker Th1 responses, there was significant genotypic variation in nematode resistance, and anthelminthic treatment enhanced Th1 immunity. Using a disease dynamic model parameterized with empirical data, we found that nematode-induced immune suppression can facilitate the invasion of bovine TB in buffalo. In the absence of nematodes, TB failed to invade the system, illustrating the critical role nematodes may play in disease establishment. Our results suggest that helminths, by influencing the likelihood of microparasite invasion, may influence patterns of disease emergence in the wild

COMPARATIVE INCIDENCE OF TUBERCULOSIS IN CANADA: THE PAST, PRESENT AND FUTURE

Canada and the United States (US) are both high income, low tuberculosis (TB) incidence countries with similar TB control programs, yet an explicit comparison of TB incidence over time is lacking. Objective one explored the impact of TB and other disease case definition change, and methods to control for the change via a general literature search. Underreporting/increases in reported cases and differences in sensitivity and specificity measures were among others noted to arise from changes in case definition. For appropriate comparisons within and between populations, consistent ascertainment criteria of cases should be adopted. Objective 2 explored and compared TB incidence rates in Canada and the US from 1953-2015. TB rate from 1953-2015 was retrieved for both countries. Joinpoint and direct standardization were performed. Canada’s TB rates/100,000 were higher from 1953-1974. Canada’s average annual percent change in rate from 1975-2015 was -2.9% compared to the US -4.1%. Case definition change, HIV+/TB co-infection, and Foreign-born (FB) TB were the main contributors to the differences. Objective three compared the rate of TB decline in subpopulations. TB cases and population by ethnicity from 2001-2011, and the percent of HIV+/TB co-infection cases from 1997-2012 were retrieved for Canada and the US. Segmented and decomposition analysis was performed. FB and Indigenous TB rate declined by -3.7% and -6.3% in the US and by -1.7% and -4.5% in Canada. Changes in age-specific rates declined overall rates in Canada by 80.1% and the US at 66.7%. Overall, the percentage of HIV+/TB cases declined more rapidly in the US than in Canada. After adjusting for age, FB and Indigenous populations, rates decline more in the US than in Canada. Objective four forecasted and then compared year-over-year TB rates between Canada and US from 2017-2035. TB rate from 1975-2016 and rates by ethnicity from 1993-2016 were retrieved for both countries. Autoregressive integrated moving average and multivariate vector autoregression models were performed. The forecasted models showed a gradually decreasing trend from 2017-2035, reaching a rate of 2.2 for Canada and 1.3 for the US by 2035. The prediction suggests that achieving 2035 WHO set target could be a challenge for both countries

Hidden Consequences of Living in a Wormy World: Nematode‐Induced Immune Suppression Facilitates Tuberculosis Invasion in African Buffalo

Most hosts are infected with multiple parasites, and responses of the immune system to co-occurring parasites may influence disease spread. Helminth infection can bias the host immune response toward a T-helper type 2 (Th2) over a type 1 (Th1) response, impairing the host’s ability to control concurrent intracellular microparasite infections and potentially modifying disease dynamics. In humans, immune-mediated interactions between helminths and microparasites can alter host susceptibility to diseases such as HIV, tuberculosis (TB), and malaria. However, the extent to which similar processes operate in natural animal populations and influence disease spread remains unknown.We used cross-sectional, experimental, and genetic studies to show that gastrointestinal nematode infection alters immunity to intracellular microparasites in free-ranging African buffalo (Syncerus caffer). Buffalo that were more resistant to nematode infection had weaker Th1 responses, there was significant genotypic variation in nematode resistance, and anthelminthic treatment enhanced Th1 immunity. Using a disease dynamic model parameterized with empirical data, we found that nematode-induced immune suppression can facilitate the invasion of bovine TB in buffalo. In the absence of nematodes, TB failed to invade the system, illustrating the critical role nematodes may play in disease establishment. Our results suggest that helminths, by influencing the likelihood of microparasite invasion, may influence patterns of disease emergence in the wild

Analysis of Dominant HIV Quasispecies Suggests Independent Viral Evolution Within Spinal Granulomas Coinfected with Mycobacterium tuberculosis and HIV-1 Subtype C

Extrapulmonary tuberculosis (TB) is a significant public health challenge in South Africa and worldwide, largely fuelled by the HIV epidemic. In spinal TB, Mycobacteria infect the spinal column without dissemination to the spinal cord. The immune microenvironment, target cell characteristics, and other evolutionary forces within granulomas during HIV/TB coinfection are poorly characterized. We investigated whether spinal TB granulomas represent a sequestered anatomical site where independent HIV evolution occurs, and assessed the role of macrophages as a target cell for both HIV and mycobacteria. RNA was extracted from plasma and granulomatous tissue from six antiretroviral-naive HIV-1/spinal TB-coinfected patients, RT-PCR amplified, and the C2-V5 env segment was cloned and sequenced. Analysis of genetic diversity, phylogeny and coalescence patterns was performed on clonal sequences. To investigate their role in HIV sequestration, macrophages and the HIV-1 p24 protein were immune localized and ultrastructural features were studied. Intercompartment diversity measurements and phylogenetic reconstruction revealed anatomically distinct monophyletic HIV-1 clusters in four of six patients. Genotypic CCR5-tropic variants were predominant (98.9%) with conservation of putative N-linked glycosylation sites in both compartments. CD68(+) reactivity was associated with higher tissue viral load (r = 1.0; p < 0.01) but not greater intrapatient diversity (r = 0.60; p > 0.05). Ultrastructural imaging revealed the presence of bacterial and virus-like particles within membrane-bound intracellular compartments of macrophages. Spinal tuberculosis granulomas may form anatomically discreet sites of divergent viral evolution. Macrophages in these granulomas harbored both pathogens, suggesting that they may facilitate the process of viral sequestration within this compartment