Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications but does not restore full health. HIV-infected adults have excess ...risk of cardiovascular, liver, kidney, bone, and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance, and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affects health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although antiretroviral therapy for HIV infection prevents AIDS-related complications and prolongs life, it does not fully restore health. Long-term treated patients remain at higher than expected ...risk for a number of complications typically associated with aging, including cardiovascular disease, cancer, osteoporosis, and other end-organ diseases. The potential effect of HIV on health is perhaps most clearly exhibited by a number of immunologic abnormalities that persist despite effective suppression of HIV replication. These changes are consistent with some of the changes to the adaptive immune system that are seen in the very old ("immunosenescence") and that are likely related in part to persistent inflammation. HIV-associated inflammation and immunosenescence have been implicated as causally related to the premature onset of other end-organ diseases. Novel therapeutic strategies aimed at preventing or reversing these immunologic defects may be necessary if HIV-infected patients are to achieve normal life span.
The success of antiretroviral therapy has led some people to now ask whether the end of AIDS is possible. For patients who are motivated to take therapy and who have access to lifelong treatment, ...AIDS-related illnesses are no longer the primary threat, but a new set of HIV-associated complications have emerged, resulting in a novel chronic disease that for many will span several decades of life. Treatment does not fully restore immune health; as a result, several inflammation-associated or immunodeficiency complications such as cardiovascular disease and cancer are increasing in importance. Cumulative toxic effects from exposure to antiretroviral drugs for decades can cause clinically-relevant metabolic disturbances and end-organ damage. Concerns are growing that the multimorbidity associated with HIV disease could affect healthy ageing and overwhelm some health-care systems, particularly those in resource-limited regions that have yet to develop a chronic care model fully. In view of the problems inherent in the treatment and care for patients with a chronic disease that might persist for several decades, a global effort to identify a cure is now underway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Intense investigation into the predictors and determinants of post-acute sequelae of SARS-CoV-2 infection (PASC), including ‘long COVID’, is underway. Recent studies provide clues to the mechanisms ...that might drive this condition, with the goal of identifying host or virus factors that can be intervened upon to prevent or reverse PASC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this brief review and perspective, we address the question of whether the immune responses that bring about immune control of acute HIV infection are the same as, or distinct from, those that ...maintain long-term viral suppression once control of viremia has been achieved. To this end, we describe the natural history of elite and post-treatment control, noting the lack of data regarding what happens acutely. We review the evidence suggesting that the two clinical phenotypes may differ in terms of the mechanisms required to achieve and maintain control, as well as the level of inflammation that persists once a steady state is achieved. We then describe the evidence from longitudinal studies of controllers who fail and studies of biologic sex (male versus female), age (children versus adults), and simian immunodeficiency virus (SIV) (pathogenic/experimental versus nonpathogenic/natural infection). Collectively, these studies demonstrate that the battle between the inflammatory and anti-inflammatory pathways during acute infection has long-term consequences, both for the degree to which control is maintained and the health of the individual. Potent and stringent control of HIV may be required acutely, but once control is established, the chronic inflammatory response can be detrimental. Interventional approaches designed to bring about HIV cure and/or remission should be nuanced accordingly.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antiretroviral therapy (ART) inhibits HIV replication but is not curative. During ART, the integrated HIV genome persists indefinitely within CD4
T cells and perhaps other cells. Here, we describe ...the mechanisms thought to contribute to its persistence during treatment and highlight findings from numerous recent studies describing the importance of cell proliferation in that process. Continued progress elucidating the biology will enhance our ability to develop effective curative interventions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Antiretroviral therapy (ART) is able to suppress HIV-1 replication indefinitely in individuals who have access to these medications, are able to tolerate these drugs, and are motivated to take them ...daily for life. However, ART is not curative. HIV-1 persists indefinitely during ART as quiescent integrated DNA within memory CD4+ T cells and perhaps other long-lived cellular reservoirs. In this Review, we discuss the role of the immune system in the establishment and maintenance of the latent HIV-1 reservoir. A detailed understanding of how the host immune system shapes the size and distribution of the viral reservoir should lead to the development of a new generation of immune-based therapeutics, which may eventually contribute to a curative intervention.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
PURPOSE OF REVIEWThe present review will highlight some of the recent findings regarding the capacity of HIV-1 to replicate during antiretroviral therapy (ART).
RECENT FINDINGSAlthough ART is highly ...effective at inhibiting HIV replication, it is not curative. Several mechanisms contribute to HIV persistence during ART, including HIV latency, immune dysfunction, and perhaps persistent low-level spread of the virus to uninfected cells (replication). The success in curing HIV will depend on efficiently targeting these three aspects. The degree to which HIV replicates during ART remains controversial. Most studies have failed to find any evidence of HIV evolution in blood, even with samples collected over many years, although a recent very intensive study of three individuals suggested that the virus population does shift, at least during the first few months of therapy. Stronger but still not definitive evidence for replication comes from a series of studies in which standard regimens were intensified with an integration inhibitor, resulting in changes in episomal DNA (blood) and cell-associated RNA (tissue). Limited drug penetration within tissues and the presence of immune sanctuaries have been argued as potential mechanisms allowing HIV to spread during ART. Mathematical models suggest that HIV replication and evolution is possible even without the selection of fully drug-resistant variants. As persistent HIV replication could have clinical consequences and might limit the efficacy of curative interventions, determining if HIV replicates during ART and why, should remain a key focus of the HIV research community.
SUMMARYResidual viral replication likely persists in lymphoid tissues, at least in a subset of individuals. Abnormal levels of immune activation might contribute to sustain virus replication.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0
HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting ...memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4(+) T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4(+) T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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