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A robust immune response is required for resistance to pulmonary tuberculosis (TB), the primary disease caused by Mycobacterium tuberculosis (Mtb). However, pharmaceutical inhibition of T cell immune checkpoint molecules can result in the rapid development of active disease in latently infected individuals, indicating the importance of T cell immune regulation. In this study, we investigated the potential role of CD200R during Mtb infection, a key immune checkpoint for myeloid cells. Expression of CD200R was consistently downregulated on CD14+ monocytes in the blood of subjects with active TB compared to healthy controls, suggesting potential modulation of this important anti-inflammatory pathway. In homogenized TB-diseased lung tissue, CD200R expression was highly variable on monocytes and CD11b+HLA-DR+ macrophages but tended to be lowest in the most diseased lung tissue sections. This observation was confirmed by fluorescent microscopy, which showed the expression of CD200R on CD68+ macrophages surrounding TB lung granuloma and found expression levels tended to be lower in macrophages closest to the granuloma core and inversely correlated with lesion size. Antibody blockade of CD200R in a biomimetic 3D granuloma-like tissue culture system led to significantly increased Mtb growth. In addition, Mtb infection in this system reduced gene expression of CD200R. These findings indicate that regulation of myeloid cells via CD200R is likely to play an important part in the immune response to TB and may represent a potential target for novel therapeutic intervention.

Only three well-characterised cases of functional cure have been described in paediatric HIV infection over the past decade. This underlines the fact that early initiation of combination antiretroviral therapy (cART), whilst minimising the size of the viral reservoir, is insufficient to achieve cure, unless other factors contribute. In this review, we consider these additional factors that may facilitate functional cure in paediatric infection. Among the early life immune activity, these include HIV-specific cytotoxic T-lymphocyte (CTL) and natural killer (NK) cell responses. The former have less potent antiviral efficacy in paediatric compared with adult infection, and indeed, in early life, NK responses have greater impact in suppressing viral replication than CTL. This fact may contribute to a greater potential for functional cure to be achieved in paediatric versus adult infection, since post-treatment control in adults is associated less with highly potent CTL activity, and more with effective antiviral NK cell responses. Nonetheless, antiviral CTL responses can play an increasingly effective role through childhood, especially in individuals expressing then ‘protective’ HLA-I molecules HLA-B*27/57/58:01/8101. The role of the innate system on preventing infection, in shaping the particular viruses transmitted, and influencing outcome is discussed. The susceptibility of female fetuses to in utero mother-to-child transmission, especially in the setting of recent maternal infection, is a curiosity that also provides clues to mechanisms by which cure may be achieved, since initial findings are that viral rebound is less frequent among males who interrupt cART. The potential of broadly neutralising antibody therapy to facilitate cure in children who have received early cART is discussed. Finally, we draw attention to the impact of the changing face of the paediatric HIV epidemic on cure potential. The effect of cART is not limited to preventing AIDS and reducing the risk of transmission. cART also affects which mothers transmit. No longer are mothers who transmit those who carry genes associated with poor immune control of HIV. In the cART era, a high proportion (>70% in our South African study) of transmitting mothers are those who seroconvert in pregnancy or who for social reasons are diagnosed late in pregnancy. As a result, now, genes associated with poor immune control of HIV are not enriched in mothers who transmit HIV to their child. These changes will likely influence the effectiveness of HLA-associated immune responses and therefore cure potential among children.

HIV infection in the human gastrointestinal (GI) tract is thought to be central to HIV progression, but knowledge of this interaction is primarily limited to cohorts within Westernized countries. Here, we present a large cohort recruited from high HIV endemic areas in South Africa and found that people living with HIV (PLWH) presented at a younger age for investigation in the GI clinic. We identified severe CD4+ T cell depletion in the GI tract, which was greater in the small intestine than in the large intestine and not correlated with years on antiretroviral treatment (ART) or plasma viremia. HIV-p24 staining showed persistent viral expression, particularly in the colon, despite full suppression of plasma viremia. Quantification of mucosal antiretroviral (ARV) drugs revealed no differences in drug penetration between the duodenum and colon. Plasma markers of gut barrier breakdown and immune activation were elevated irrespective of HIV, but peripheral T cell activation was inversely correlated with loss of gut CD4+ T cells in PLWH alone. T cell activation is a strong predictor of HIV progression and independent of plasma viral load, implying that the irreversible loss of GI CD4+ T cells is a key event in the HIV pathogenesis of PLWH in South Africa, yet the underlying mechanisms remain unknown.

SARS-CoV-2 infects epithelial cells of the human gastrointestinal (GI) tract and causes related symptoms. HIV infection impairs gut homeostasis and is associated with an increased risk of COVID-19 fatality. To investigate the potential link between these observations, we analyzed single-cell transcriptional profiles and SARS-CoV-2 entry receptor expression across lymphoid and mucosal human tissue from chronically HIV-infected individuals and uninfected controls. Absorptive gut enterocytes displayed the highest coexpression of SARS-CoV-2 receptors ACE2, TMPRSS2, and TMPRSS4, of which ACE2 expression was associated with canonical interferon response and antiviral genes. Chronic treated HIV infection was associated with a clear antiviral response in gut enterocytes and, unexpectedly, with a substantial reduction of ACE2 and TMPRSS2 target cells. Gut tissue from SARS-CoV-2–infected individuals, however, showed abundant SARS-CoV-2 nucleocapsid protein in both the large and small intestine, including an HIV-coinfected individual. Thus, upregulation of antiviral response genes and downregulation of ACE2 and TMPRSS2 in the GI tract of HIV-infected individuals does not prevent SARS-CoV-2 infection in this compartment. The impact of these HIV-associated intestinal mucosal changes on SARS-CoV-2 infection dynamics, disease severity, and vaccine responses remains unclear and requires further investigation.

An on-road study was conducted to evaluate a complementary tactile navigation signal on driving behaviour and eye movements for drivers with hearing loss (HL) compared to drivers with normal hearing (NH). 32 participants (16 HL and 16 NH) performed two preprogrammed navigation tasks. In one, participants received only visual information, while the other also included a vibration in the seat to guide them in the correct direction. SMI glasses were used for eye tracking, recording the point of gaze within the scene. Analysis was performed on predefined regions. A questionnaire examined participant's experience of the navigation systems. Hearing loss was associated with lower speed, higher satisfaction with the tactile signal and more glances in the rear view mirror. Additionally, tactile support led to less time spent viewing the navigation display.