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A novel immunization strategy using cytokine/chemokines induces new effective systemic immune responses, and frequent complete regressions of human metastatic melanoma

Valentine, Fred T; Golomb, Frederick M; Harris, Matthew; Roses, Daniel F
Immune responses have been elicited by a variety of cancer vaccines, but seldom induce regressions of established cancers in humans. As a novel therapeutic immunization strategy, we tested the hypothesis that multiple cytokines/chemokines secreted early in secondary responses ex-vivo might mimic the secretory environment guiding new immune responses. The early development of immune responses is regulated by multiple cytokines/chemokines acting together, which at physiologic concentrations act locally in concert with antigen to have non-specific effects on adjacent cells, including the maturation of dendritic cells, homing and retention of T cells at the site of antigen, and the differentiation and expansion of T cell clones with appropriate receptors. We postulated that repeated injections into a metastasis of an exogenous chemokine/cytokine mixture might establish the environment of an immune response and allow circulating T cell clones to self- select for mutant neo-epitopes in the tumor and generate systemic immune responses. To test this idea we injected some metastases in patients with multiple cutaneous melanoma nodules while never injecting other control metastases in the same patient. New immune responses were identified by the development of dense lymphocytic infiltrates in never-injected metastases, and the frequent complete regression of never-injected metastases, a surprising observation. 70% of subjects developed dense infiltrates of cytotoxic CD8 cells in the center and margin of never-injected metastases; 38% of subjects had complete and often durable regressions of all metastases, without the use of check-point inhibitors, suggesting that, as a proof-of-principle, an immunization strategy can control advanced human metastatic melanoma.
PMID: 29308310
ISSN: 2162-4011
CID: 2905762

Epigenetic mechanisms, T-cell activation, and CCR5 genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor

Gornalusse, German G; Mummidi, Srinivas; Gaitan, Alvaro A; Jimenez, Fabio; Ramsuran, Veron; Picton, Anabela; Rogers, Kristen; Manoharan, Muthu Saravanan; Avadhanam, Nymisha; Murthy, Krishna K; Martinez, Hernan; Molano Murillo, Angela; Chykarenko, Zoya A; Hutt, Richard; Daskalakis, Demetre; Shostakovich-Koretskaya, Ludmila; Abdool Karim, Salim; Martin, Jeffrey N; Deeks, Steven G; Hecht, Frederick; Sinclair, Elizabeth; Clark, Robert A; Okulicz, Jason; Valentine, Fred T; Martinson, Neil; Tiemessen, Caroline Tanya; Ndung'u, Thumbi; Hunt, Peter W; He, Weijing; Ahuja, Sunil K
T-cell expression levels of CC chemokine receptor 5 (CCR5) are a critical determinant of HIV/AIDS susceptibility, and manifest wide variations (i) between T-cell subsets and among individuals and (ii) in T-cell activation-induced increases in expression levels. We demonstrate that a unifying mechanism for this variation is differences in constitutive and T-cell activation-induced DNA methylation status of CCR5 cis-regulatory regions (cis-regions). Commencing at an evolutionarily conserved CpG (CpG -41), CCR5 cis-regions manifest lower vs. higher methylation in T cells with higher vs. lower CCR5 levels (memory vs. naive T cells) and in memory T cells with higher vs. lower CCR5 levels. HIV-related and in vitro induced T-cell activation is associated with demethylation of these cis-regions. CCR5 haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status of CCR5 intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protective CCR5-HHA haplotype bears a polymorphism at CpG -41 that is (i) specific to southern Africa, (ii) abrogates binding of the transcription factor CREB1 to this cis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking the CCR5-Delta32 mutation but with hypermethylated cis-regions have CCR5 levels similar to genotypes heterozygous for CCR5-Delta32. In HIV-infected individuals, CCR5 cis-regions remain demethylated, despite restoration of CD4+ counts (>/=800 cells per mm(3)) with antiretroviral therapy. Thus, methylation content of CCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes.
PMID: 26307764
ISSN: 1091-6490
CID: 1742172

Structural Characterization of Two Monoclonal Antibodies Targeting the Fourth Constant Domain in the Bridging Sheet of HIV-1 gp120 [Meeting Abstract]

Pan, R. ; Chen, Y. ; Vaine, M. ; Wang, S. ; Kelker, H. C. ; Itri, V. R. ; Valentine, F. T. ; Lu, S. ; Kong, X.
ISSN: 0889-2229
CID: 657002

Early Detection of HIV Infection Among Kenyan Infants Using a Reverse Transcriptase Activity Assay

Sivapalasingam, Sumathi; Ahmed, Aabid; Mendillo, Megan; Holzman, Robert; Marshed, Fatuma; Mwamzuka, Musa; Khamadi, Samuel; Mwau, Matilu; Laverty, Maura; Valentine, Fred
Two hundred HIV-exposed Kenyan infants were tested for HIV infection at birth and at age 6, 12, 24 and 48 weeks, by DNA polymerase chain reaction (PCR) and Cavidi reverse transcriptase (RT) assays and after age 18 months by HIV antibody test. Eleven (5.5%) infants became HIV infected. In 6 infants, positive RT preceded positive DNA PCR. The use of RT assay may facilitate earlier HIV diagnosis in infants.
PMID: 22581226
ISSN: 0891-3668
CID: 169479

Sex differences in the incidence of peripheral neuropathy among kenyans initiating antiretroviral therapy

Mehta, Sapna A; Ahmed, Aabid; Laverty, Maura; Holzman, Robert S; Valentine, Fred; Sivapalasingam, Sumathi
Background. Peripheral neuropathy (PN) is common among patients receiving antiretroviral therapy (ART) in resource-limited settings. We report the incidence of and risk factors for PN among human immunodeficiency virus (HIV)-infected Kenyan adults initiating ART. Methods. An inception cohort was formed of adults initiating ART. They were screened for PN at baseline and every 3 months for 1 year. We used the validated Brief Peripheral Neuropathy Screen (BPNS) that includes symptoms and signs (vibration perception and ankle reflexes) of PN. Results. Twenty-two (11%) of 199 patients had PN at baseline screening. One hundred fifty patients without evidence of PN at baseline were followed for a median of 366 days (interquartile range, 351-399). The incidence of PN was 11.9 per 100 person-years (95% confidence interval [CI], 6.9-19.1) and was higher in women than men (17.7 vs 1.9 per 100 person-years; rate ratio, 9.6; 95% CI, 1.27-72, P = .03). In stratified analyses, female sex remained statistically significant after adjustment for each of the following variables: age, CD4 cell count, body mass index, ART regimen, and tuberculosis treatment. Stratifying hemoglobin levels decreased the hazard ratio from 9.6 to 7.40 (P = .05), with higher levels corresponding to a lower risk of PN. Conclusions. HIV-infected Kenyan women were almost 10 times more likely than men to develop PN in the first year of ART. The risk decreased slightly at higher hemoglobin levels. Preventing or treating anemia in women before ART initiation and implementing BPNS during the first year of ART, the period of highest risk, could ameliorate the risk of PN
PMID: 21844033
ISSN: 1537-6591
CID: 136612

Evidence of dysregulation of dendritic cells in primary HIV infection

Sabado, Rachel Lubong; O'Brien, Meagan; Subedi, Abhignya; Qin, Li; Hu, Nan; Taylor, Elizabeth; Dibben, Oliver; Stacey, Andrea; Fellay, Jacques; Shianna, Kevin V; Siegal, Frederick; Shodell, Michael; Shah, Kokila; Larsson, Marie; Lifson, Jeffrey; Nadas, Arthur; Marmor, Michael; Hutt, Richard; Margolis, David; Garmon, Donald; Markowitz, Martin; Valentine, Fred; Borrow, Persephone; Bhardwaj, Nina
Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV in-fection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation
PMID: 20693428
ISSN: 1528-0020
CID: 114507

Implementation of a validated peripheral neuropathy screening tool in patients receiving antiretroviral therapy in mombasa, kenya

Mehta, Sapna A; Ahmed, Aabid; Kariuki, Beatrice W; Said, Swaleh; Omasete, Fanuel; Mendillo, Megan; Laverty, Maura; Holzman, Robert; Valentine, Fred; Sivapalasingam, Sumathi
Limited objective data are available for the prevalence of peripheral neuropathy (PN) among antiretroviral (ART)-treated human immunodeficiency virus (HIV)-infected patients in resource-limited settings. A validated neuropathy-screening tool was integrated into routine ART visits at an HIV clinic in Mombasa, Kenya. Diagnosis of PN required at least one symptom and either abnormal vibratory sensation or deep tendon reflex bilaterally. Among 102 consecutively screened patients, 63% were women, 62% were receiving ART for </= 1 year, and 86% were receiving a stavudine (D4T)-based regimen. Thirty-seven (36%) had PN. Univariate analysis showed that current D4T use was protective against PN (P = 0.03) and older age was a marginal risk factor (P = 0.05). Multivariate analysis showed that older age was a risk factor for neuropathy (P = 0.04). Peripheral neuropathy was common, particularly among older HIV-infected adults in Kenya. The protective association with current D4T use likely represents survivor effect bias. Longitudinal studies using this screen will help further characterize PN in resource-limited settings
PMID: 20810821
ISSN: 1476-1645
CID: 112054

Susceptibility of Human Th17 Cells to Human Immunodeficiency Virus and Their Perturbation during Infection

El Hed, Aimee; Khaitan, Alka; Kozhaya, Lina; Manel, Nicolas; Daskalakis, Demetre; Borkowsky, William; Valentine, Fred; Littman, Dan R; Unutmaz, Derya
Background. Identification of the Th17 T cell subset as important mediators of host defense and pathology prompted us to determine their susceptibility to human immunodeficiency virus (HIV) infection. Methods and results. We found that a sizeable portion of Th17 cells express HIV coreceptor CCR5 and produce very low levels of CCR5 ligands macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. Accordingly, CCR5(+) Th17 cells were efficiently infected with CCR5-tropic HIV and were depleted during viral replication in vitro. Remarkably, HIV-infected individuals receiving treatment had significantly reduced Th17 cell counts, compared with HIV-uninfected subjects, regardless of viral load or CD4 cell count, whereas treatment-naive subjects had normal levels. However, there was a preferential reduction in CCR5(+) T cells that were also CCR6 positive, which is expressed on all Th17 cells, compared with CCR6(-)CCR5(+) cells, in both treated and untreated HIV-infected subjects. This observation suggests preferential targeting of CCR6(+)CCR5(+) Th17 cells by CCR5-tropic viruses in vivo. Th17 cell levels also inversely correlated with activated CD4(+) T cells in HIV-infected individuals who are receiving treatment. Conclusions. Our findings suggest a complex perturbation of Th17 subsets during the course of HIV disease potentially through both direct viral infection and virus indirect mechanisms, such as immune activation
PMID: 20144043
ISSN: 0022-1899
CID: 107380

The Development and Implementation of an Outreach Program to Identify Acute and Recent HIV Infections in New York City

Silvera, Richard; Stein, Dylan; Hutt, Richard; Hagerty, Robert; Daskalakis, Demetre; Valentine, Fred; Marmor, Michael
INTRODUCTION: Since 2004, the authors have been operating First Call NYU, an outreach program to identify acute and recent HIV infections, also called primary HIV infections, among targeted at-risk communities in the New York City (NYC) metropolitan area. MATERIALS AND METHODOLOGY: First Call NYU employed mass media advertising campaigns, outreach to healthcare providers in NYC, and Internet-based efforts including search engine optimization (SEO) and Internet-based advertising to achieve these goals. RESULTS: Between October 2004 and October 2008, 571 individuals were screened through this program, leading to 446 unique, in-person screening visits. 47 primary HIV infections, including 14 acute and 33 recent HIV infections, were identified. DISCUSSION: Internet and traditional recruitment methods can be used to increase self-referrals for screening following possible exposure to HIV. CONCLUSION: Community education of at-risk groups, with the goal of increased self-diagnosis of possible acute HIV infection, may be a useful addition to traditional efforts to identify such individuals
PMID: 20386719
ISSN: 1874-6136
CID: 109049

Measurement of antiretroviral drugs in the lungs of HIV-infected patients

Twigg HL; Schnizlein-Bick CT; Weiden M; Valentine F; Wheat J; Day RB; Rominger H; Zheng L; Collman RG; Coombs RW; Bucy RP; Rezk NL; Kashuba AD
AIMS: Prior studies have shown that HAART is associated with decreased HIV viral load in the lungs. The correlation between antiretroviral exposure in bronchoalveolar lavage (BAL) fluid and virologic response was evaluated in patients starting HAART and enrolled in The AIDS Clinical Trial Group Protocol 723. MATERIALS #ENTITYSTARTX00026; METHODS: A total of 24 subjects underwent blood and BAL sampling prior to starting HAART, and after 4 and 24 weeks of HAART. Drug concentrations and HIV RNA were measured in paired plasma and BAL samples. RESULTS: Antiretroviral drugs, including efavirenz, were detectable in BAL fluid of HIV-infected subjects beginning HAART. Efavirenz was also associated with a higher likelihood of clearing HIV RNA from the lungs. CONCLUSION: These results suggest the excellent pulmonary virologic response to antiretroviral therapy may, in part, be due to penetration of antiretroviral drugs into the alveolar compartment
PMID: 20436781
ISSN: 1758-4329
CID: 138270