ZIA BC 011058 (ZIA) | |||
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Title | Development of a Vaccine for HIV-AIDS: Humoral Immunity | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Robert-Guroff, Marjorie | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,180,923 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Kaposi Sarcoma (30.0%) Non Hodgkins Lymphoma (40.0%) Sarcoma (30.0%) |
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Research Type | |||
Exogenous Factors in the Origin and Cause of Cancer Vaccines |
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Abstract | |||
Immunization with live, replication-competent Ad-HIV or Ad-SIV recombinant vaccines primes strong antibody responses that develop following administration of booster immunizations with envelope protein. These antibodies display many functional activities. The most desirable for an HIV/AIDS vaccine is broadly neutralizing activity that can prevent infection following exposure to multiple ""clades"" or subtypes of the virus that circulate worldwide. However, neither this vaccine approach or others has been able to elicit such antibodies. More readily induced antibodies lack neutralizing activity but broadly react with multiple viral isolates and mediate effector functions via interaction with Fc receptors on a variety of cell types. HIV/SIV infection is initially manifested as small foci of infected cells. Within 2-6 days, virus spreads from these cell foci to draining lymph nodes, leading to systemic infection. The non-neutralizing functional antibody activities can help control the initial viral burden by limiting the spread of virus from the foci of infection. Our replicating Ad-recombinant prime/envelope boost vaccine regimen elicits such activities including antibody dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and have associated them with vaccine-induced protective efficacy in SIV and chimeric SHIV Rhesus macaque models which appropriately mimic HIV infection in people. Recently we investigated another non-neutralizing activity, antibody-dependent complement mediated lysis (ADCML). We found that antibodies induced by our vaccine regimen mediated ADCML of both SIV virions and SIV-infected cells. Further, a modest correlation of ADCML lysis of SIV virions with reduced infection rate was seen in males but not females. This prompted us to look in greater depth at ADCML activity between the sexes. Gag-specific IgG and gp120-specific IgG and IgM correlated with SIV lysis in females while Env-specific IgM correlated with SIV-infected cell lysis in males indicating sex differences in vaccine-induced antibody characteristics and function. In fact, viral envelope-specific antibody functional correlates between ADCC, ADCP, and ADCML varied depending on the sex of the vaccinees. Additionally, glycosylation of antibody Fc regions differed between males and females and influenced corresponding functional activities. This latter result not only suggests mechanisms that can be employed to modify antibody functional activity, but also continues to indicate the importance of evaluating vaccine-induced responses in both sexes. We had previously shown a sex bias in response to SIV vaccination, with females but not males exhibiting delayed infection following repeated low-dose challenges to SIV. This previous outcome was associated with local mucosal immunity. The current result extends the mechanisms associated with the vaccine-induced sex bias to additional systemic immune responses. Overall, these data continue to suggest that sex influences vaccine-induced antibody function and should be considered in design of globally-effective HIV vaccines in the future. This is an important issue as approximately 50% percent of HIV infected people worldwide are women. We are continuing exploration of the sex bias by transcriptome analysis and analysis of the microbiome. We are studying individual cell types in order to further understand their contribution to overall vaccine-induced immunity. Neutrophils are the most prevalent leukocyte and exert considerable influence on the innate immune response, with increasing evidence that they also contribute substantially to adaptive immunity. Their innate functionality entails the release of a vast array of cytokines and chemokines. They are stimulated by various chemoattractants and subsequently traffic to sites of inflammation, where they can kill invading pathogens via phagocytosis, degranulation, or by releasing neutrophil extracellular traps (NETs). They contri |