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Novel Approaches Toward a Cure for HIV and Oral Opportunistic Pathogens

AIDS and Immunosuppression Program
Integrative Biology and Infectious Diseases Branch
Division of Extramural Research 


OBJECTIVE:
In spite of significant accomplishments after 30 years of research on HIV and the global AIDS epidemic, a functional or permanent cure for HIV and its oral infectious comorbidities has yet to be achieved. For this reason, the goal of this initiative is to support novel basic and translational research projects that will advance our understanding of the polymicrobial, immunological and pathophysiological basis of functional or permanent cure for HIV and its oral infectious comorbidities. Specifically, this initiative will stimulate research to:
 
  • Define mechanisms associated with the control of persistence, dissemination, pathogen glycosylation and epigenetic modification, eradication of reservoirs, and reactivation of HIV and oral opportunistic pathogens in latently infected oral cells and tissues to attenuate pathogenicity and induce immunoclearance
  • Delineate the impact of oral immune activation and inflammation in the establishment and spread of HIV and oral opportunistic infections, and in the formation of reservoirs in oral cells and tissues
  • Identify oral host restriction factors as well as immune and molecular (i.e., genetic, epigenetic and glycomic) mechanisms for the control and eradication of HIV and oral opportunistic infections in the presence and absence of therapies
  • Test novel drugs and approaches to eradicate HIV/AIDS-related oral pathogen reservoirs as well as strategies to control their pathogenicity
  • Identify and validate novel assays to measure latently infected oral cells and tissues, pathogen reactivation and persistent AIDS-related infections in the oral cavity
  • Optimize animal and oral cell/tissue models to predict immune control and eradication of HIV and oral opportunistic infections

The outcome of this initiative will be the generation of knowledge to enable the development of interventions to functionally or permanently cure HIV and AIDS-related oral infections. This initiative will support research projects that investigate oral diseases caused by, but that are not limited to the following oral pathogens: HIV, Herpes Simplex Virus, Human Papillomavirus, Kaposi’s Sarcoma Virus, Epstein Barr Virus, Polyomaviruses, Cytomegalovirus, and fungal and bacterial species.

BACKGROUND:
The concept of functional or permanent cure for HIV derives from two recently reported clinical cases. First, the “Berlin HIV infected patient” who received a bone marrow transplant with HIV-resistant hematopoietic stem cells in combination with suppressive antiretroviral therapy (ART) has been functionally cured for five years. Second, the Mississippi HIV-infected infant who received antiretroviral therapy (ART) 30 hours after birth followed by treatment interruption at 18 months is also functionally cured; that is, she has lived for over one year with no measurable viral RNA in the blood in spite of not receiving ART. In general, the functional or permanent cure for HIV focuses on the possibility of reaching immune control of viral replication from latently infected reservoirs through therapy induced viral reactivation, followed by immunoclearance. The latter eradicates virus-expressing cells by the host’s immune system partially (i.e., functionally decreasing viral load) in the infected host, or completely (i.e., permanently) freeing the host from HIV infection.

While the overall goal is to purge HIV from reservoirs using combined strategies to cure the infection and prevent progression to AIDS with its associated comorbidities, it is unclear how to effectively and globally achieve this objective with the current state of the science. Thus, there is a need to develop new therapies and clinical strategies, which have the potential to treat and cure HIV and oral opportunistic infections. To this end, complex, multimodal strategies are being tested to tackle the viral life cycle at several stages and to enhance the host’s immunity. Improving reservoir penetrability by using combined antiretroviral therapy (cART) with other drugs, and enhancing the host’s molecular and immune responses represents the general approach toward a cure for HIV/AIDS. Specifically, the host molecular and immune response approaches used in combination with cART and other drugs are: testing novel genomic, proteomic, epigenomic or functional glycomic strategies to attenuate viral pathogenicity; boosting immunity with immune-based therapies (e.g., targeting apoptotic regulatory pathways; restoring CD4+ T cells; using cytokines alone or as adjuvants in therapeutic vaccines, and enhancing CD8+ T cell responses); decreasing inflammation and activation of latency; controlling chronic immune activation and immune dysfunction; understanding the mechanisms by which HIV controllers spontaneously restrain viral replication even in the absence of ART; and understanding mechanisms of the immunological synapse critical for T-cell activation and establishment of T-cell memory in the context of HIV persistence.

By analogy to HIV, functional or permanent cure for oral opportunistic pathogens causing oral diseases is conceivable, if key knowledge were available to understand and target the central mechanisms linked to the persistence of these pathogens in oral reservoirs. For instance, it has been extensively reported that these oral pathogens are secreted in saliva with or without the development of oral diseases. However, the mechanisms for the persistence and eradication of these oral pathogens are unknown. It is plausible that novel strategies being tested in the context of HIV may guide similar approaches for the eradication of opportunistic pathogens causing oral diseases in HIV/AIDS infected individuals.

Examples of research topics supported by this initiative include but are not limited to: 

  • Characterizing host’s molecular and immune factors and mechanisms linked to the eradication of HIV and opportunistic pathogens in oral reservoirs
  • Testing of novel therapies such as immune-based (i.e., cytokine and/or vaccine) therapies along with cARTs with improved reservoir penetrability and concentration for eradication of HIV and oral opportunistic pathogens
  • Assessing strategies for gene therapy, boosting HIV and oral opportunistic pathogen specific immune responses, and reducing inflammation and activation of latency
  • Understanding mechanisms by which HIV and oral opportunistic pathogens induce apoptosis of infected cells to induce cell death and immunoclearance in the oral cavity, and determining mechanisms by which some infected cells escape from pro-apoptotic effects of productive pathogen infection
  • Elucidating the genomic, epigenomic and glycomic host mechanisms that control HIV and oral opportunistic pathogen replication in the absence of therapy
  • Establishing novel in vitro and in vivo models of HIV and oral pathogen latency to assess changes in functional transcriptomics, proteomics, epigenomics and glycomics linked to controlling the processes of pathogen entry, maintenance and reactivation of latency in oral cells and tissues
  • Testing novel approaches designed to limit the early establishment of oral pathogen reservoirs, to eliminate infected cells, or to avoid replenishment of these reservoirs to lead to HIV remission in the absence of therapy

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This page last updated: February 26, 2014