Biology subjects

McMahon, D.

Publications and source records attributed to McMahon, D..

3 recordsLinked to original sources

bioRxiv2022

Reduction of the HIV-1 reservoir in T cells from persons with HIV-1 on suppressive antiretroviral therapy using expanded natural killer cells ex vivo

Treatment with latency-reversing agents (LRAs) alone has been ineffective in reducing HIV-1 reservoirs in persons with HIV-1 (PWH) on antiretroviral therapy (ART), due to inefficiencies in reservoir reactivation and adaptive immune responses. However, NK cells that are activated with cytokines may be able to target HIV-1 reservoirs more efficiently. To study the therapeutic potential of NK cells, we expanded blood NK cells from multiple donors ex vivo into CD56brightCD16+ "eNK" cells using artificial antigen presenting cells (aAPCs) expressing membrane-bound IL21. eNK cells express multiple activating receptors and are highly cytotoxic against specific target cells. eNK cells can also kill HIV-infected CD4 T cells via antibody dependent cell-mediated cytotoxicity (ADCC) using broadly neutralizing antibodies against HIV-1 Env gp120/gp41. Importantly, eNK cells from PWH on ART efficiently killed autologous HIV-1+ T cells reactivated by a combination of vorinostat (SAHA) and IL-15 or an IL-15 superagonist (N-803), as detected by declines in proviral load, inducible HIV-1 mRNA, and virus release. Adoptive immunotherapy with eNK cells is therefore a promising approach to reduce the latent HIV-1 reservoir in PWH when combined with LRA treatment. Author SummarySuccessful antiretroviral therapy (ART) eliminates progression to AIDS by reducing HIV to nearly indetectable levels by routine clinical measurements of blood samples. However, more sensitive DNA and RNA measurements show that most persons on ART retain a reservoir of long lived latently infected cells, which remain undetected by the immune system while no HIV is being produced. In nearly all cases, ART interruption results in a rebound of HIV production and spread, requiring an immediate return to ART. Currently the goal of HIV eradication is to achieve a "functional cure", where HIV reservoirs are reduced to the point where ART can be interrupted indefinitely, and low levels of infected cells remaining can be controlled by the immune system. Our eradication strategy combines HIV latency-reversing agents (LRAs), ex vivo expansion of natural killer (NK) cells, and enhancement of specificity and killing of infected cells with broadly neutralizing antibodies against HIV. In this study, we have demonstrated that NK cells from person living with HIV can be isolated and expanded ex vivo into "eNK" cells that kill HIV-infected cells without killing uninfected cells, especially when broadly neutralizing antibodies are present, and can significantly reduce HIV reservoirs after LRA treatment.

immunology↗

bioRxiv2020

HIV-specific T-cell responses reflect substantive in vivo interactions with infected cells despite long-term therapy

Antiretroviral therapies (ART) durably suppress HIV replication to undetectable levels - however, infection persists in the form of long-lived reservoirs of infected cells with integrated proviruses, that re-seed systemic replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in driving reductions in viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle, by querying the dynamics of HIV-specific T-cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. We show that T-cell responses to autologous reservoir viruses persist over years, and that the maintenance of HIV-Nef-specific responses was uniquely associated with residual frequencies of infected cells. These responses disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV-infected cells. These results indicate substantial visibility of the HIV reservoir to T-cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing HIV infection.

immunology↗

bioRxiv2019

Eating in a losing cause: anorexia and macronutrient manipulation by a cockroach fails to boost immunity

BackgroundHost-pathogen interactions can lead to dramatic changes in host feeding behaviour. One aspect of this includes self-medication, where infected individuals consume substances such as toxins or alter their macronutrient consumption to enhance immune competence. Another widely adopted animal response to infection is illness-induced anorexia, which is thought to assist host immunity directly or by limiting the nutritional resources available to pathogens. Here, we recorded macronutrient preferences of the global pest cockroach, Blatta orientalis to investigate how shifts in host macronutrient dietary preference and quantity of carbohydrate (C) and protein (P) interact with immunity following bacterial infection. ResultsWe find that B. orientalis avoids diets enriched for P under normal conditions, and that high P diets reduce cockroach survival in the long term. However, following bacterial challenge, cockroaches significantly reduced their overall nutrient intake, particularly of carbohydrates, and increased the relative ratio of protein (P:C) consumed. Surprisingly, these behavioural shifts had a limited effect on cockroach immunity and survival, with minor changes to immune protein abundance and antimicrobial activity between individuals placed on different diets, regardless of infection status. ConclusionsWe show that cockroach feeding behaviour can be modulated by a pathogen, resulting in an illness-induced anorexia-like feeding response and a shift from a C-enriched to a more P:C equal diet. However, our results also indicate that such responses do not provide significant immune protection in B. orientalis, suggesting that the hosts dietary shift might also result from random rather than directed behaviour. The lack of an apparent benefit of the shift in feeding behaviour highlights a possible reduced importance for diet in immune regulation in these invasive animals, although further investigations employing pathogens with alternative infection strategies are warranted.

ecology↗