Llewellyn, Nick
Zioni, Rafael
Zhu, Haiying
Andrus, Thomas
Xu, Younong
Corey, Lawrence
Zhu, Tuofu
The role of blood monocytes in HIV-1 infection is a relatively new field of interest. What happens to HIV-1 in monocytes and their relationship to CD4+ T cells before, during, and after suppressive antiretroviral therapy (ART) is largely unstudied. Here, considering that diversity is a good indicator of continued replication over time, we evaluated the effect of ART on HIV-1 in blood monocytes and CD4+ T cells by examining the diversity of HIV-1 from 4 infected patients who underwent and stopped therapy. We determined diversity and compartmentalization of HIV-1 between blood monocytes and CD4+ T cells in each patient in relationship to their ART regimens. Our data indicate that the rate of HIV-1 diversity increase m monocytes during therapy was significantly higher than in CD4+ T cells (P < 0.05), suggesting that HIV-1 present in monocytes diversify more during therapy than in CD4+ T cells. Increased rates of HIV-1 compartmentalization between monocytes and CD4+ T cells while on therapy were also observed. These results suggest that ART inhibits HIV-1 replication in CD4+ T cells more than in blood monocytes and that better treatments to combat HIV-1 in monocytes/macrophages may be needed for a more complete suppression of HIV replication. J. Leukoc. Biol. 80: 1118-1126;2006.
Chien, Jason W.
Kuypers, Jane
Englund, Janet A.
Wald, Anna
Guthrie, Katherine A.
Corey, Lawrence
Boeckh, Michael
Background. Few data exist on respiratory virus quantitation in lower respiratory samples and detection in serum from hematopoietic cell transplant (HCT) recipients with respiratory virus-associated pneumonia.Methods. We retrospectively identified HCT recipients with respiratory syncytial virus (RSV), parainfluenza virus, influenza virus, metapneumovirus (MPV), and coronavirus (CoV) detected in bronchoalveolar lavage (BAL) samples, and we tested stored BAL and/or serum samples by quantitative polymerase chain reaction.Results. In 85 BAL samples from 82 patients, median viral loads were as follows: for RSV (n = 35), 2.6 x 10(6) copies/mL; for parainfluenza virus (n = 35), 4.9 x 10(7) copies/mL; for influenza virus (n = 9), 6.8 x 10(5) copies/mL; for MPV (n = 7), 3.9 x 10(7) copies/mL; and for CoV (n = 4), 1.8 x 10(5) copies/mL. Quantitative viral load was not associated with mechanical ventilation or death. Viral RNA was detected in serum samples from 6 of 66 patients: 4 of 41 with RSV pneumonia, 1 with influenza B, and 1 with MPV/influenza A virus/CoV coinfection (influenza A virus and MPV RNA detected). RSV detection in serum was associated with high viral load in BAL samples (P = .05), and viral RNA detection in serum was significantly associated with death (adjusted rate ratio, 1.8; P = .02).Conclusion. Quantitative polymerase chain reaction detects high viral loads in BAL samples from HCT recipients with respiratory virus pneumonia. Viral RNA is also detectable in the serum of patients with RSV, influenza, and MPV pneumonia and may correlate with the severity of disease.
Liu, Yi
Woodward, Amanda
Zhu, Haiying
Andrus, Thomas
McNevin, John
Lee, Jean
Mullins, James I.
Corey, Lawrence
McElrath, M. Juliana
Zhu, Tuofu
Understanding the mechanisms underlying potential altered susceptibility to human immunodeficiency virus type 1 (HIV-1) infection in highly exposed seronegative (ES) individuals and the later clinical consequences of breakthrough infection can provide insight into strategies to control HIV-1 with an effective vaccine. From our Seattle ES cohort, we identified one individual (LSC63) who seroconverted after over 2 years of repeated unprotected sexual contact with his HIV-1-infected partner (P63) and other sexual partners of unknown HIV-1 serostatus. The HIV-1 variants infecting LSC63 were genetically unrelated to those sequenced from P63. This may not be surprising, since viral load measurements in P63 were repeatedly below 50 copies/ml, making him an unlikely transmitter. However, broad HIV-1-specific cytotoxic T-lymphocyte (CTL) responses were detected in LSC63 before seroconversion. Compared to those detected after seroconversion, these responses were of lower magnitude and half of them targeted different regions of the viral proteome. Strong HLA-B27-restricted CTLs, which have been associated with disease control, were detected in LSC63 after but not before seroconversion. Furthermore, for the majority of the protein-coding regions of the HIV-1 variants in LSC63 (except gp41, nef, and the 3' half of pol), the genetic distances between the infecting viruses and the viruses to which he was exposed through P63 (termed the exposed virus) were comparable to the distances between random subtype B HIV-1 sequences and the exposed viruses. These results suggest that broad preinfection immune responses were not able to prevent the acquisition of HIV-1 infection in LSC63, even though the infecting viruses were not particularly distant from the viruses that may have elicited these responses.
Zuckerman, Richard A.
Lucchetti, Aldo
Whittington, William L. H.
Sanchez, Jorge
Coombs, Robert W.
Zuniga, Rosario
Magaret, Amalia S.
Wald, Anna
Corey, Lawrence
Celum, Connie
Background. Herpes simplex virus type 2 (HSV-2) infection is common among human immunodeficiency virus (HIV)-infected persons, and HSV reactivation increases plasma and genital HIV-1 levels. We studied HIV-1 levels during HSV suppression in coinfected persons in a placebo-controlled crossover trial. Methods. Twenty antiretroviral therapy (ART)-naive HIV-1/ HSV-2-seropositive men who have sex with men in Lima, Peru, with CD4 cell counts > 200 cells/mu L were randomized to receive either valacyclovir at 500 mg twice daily or placebo for 8 weeks, after which they underwent a 2-week washout period and then received the alternative regimen for 8 weeks. Specimens included daily anogenital swabs (for HSV DNA polymerase chain reaction [PCR]), thrice weekly rectal mucosal secretions (for HIV-1 RNA and HSVDNAPCR) obtained by anoscopy, and weekly plasma (for HIV-1 RNA PCR). Outcomes were rectal and plasma HIV-1 RNA levels by treatment arm. Results. HIV-1 was detected in 73% of 844 rectal and 99% of 288 plasma specimens. HSV was detected in 29% and 4% of mucocutaneous specimens obtained during placebo and valacyclovir administration, respectively (P <.001). Valacyclovir resulted in a 0.16 (95% confidence interval [CI], 0.07-0.25; P =.0008; 33% decrease) log(10) copies/ mL lower mean within-subject rectal HIV-1 level and a 0.33 (95% CI, 0.23-0.42; P <.0001; 53% decrease) log10 copies/ mL lower plasma HIV-1 level, compared with values for placebo. Conclusions. Valacyclovir significantly reduces rectal and plasma HIV-1 levels in HIV-1/ HSV-2-coinfected men. HSV suppression may provide clinical benefits to persons not receiving highly active ART as well as public health benefits. Trial registration. ClinicalTrials. gov identifier: NCT00378976.
Mayer, Kenneth H
Seaton, Kelly E
Huang, Yunda
Grunenberg, Nicole
Isaacs, Abby
Allen, Mary
Ledgerwood, Julie E
Frank, Ian
Sobieszczyk, Magdalena E
Baden, Lindsey R
Rodriguez, Benigno
Van Tieu, Hong
Tomaras, Georgia D
Deal, Aaron
Goodman, Derrick
Bailer, Robert T
Ferrari, Guido
Jensen, Ryan
Hural, John
Graham, Barney S
Mascola, John R
Corey, Lawrence
Montefiori, David C
BACKGROUND: VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed.; METHODS AND FINDINGS: HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18-50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n =3D 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n =3D 20); placebo (placebo group 3 [P3], n =3D 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n =3D 20). Treatment groups T4 and T5 (n =3D 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities, nor evidence for anti-VRC01 antibodies observed. Serum VRC01 levels were detected through 12 weeks after final administration in all participants who received all scheduled doses. Mean peak serum VRC01 levels of 1,177 mug/ml (95% CI: 1,033, 1,340) and 420 mug/ml (95% CI: 356, 494) were achieved 1 hour after the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively. Mean trough levels at week 24 in the IV infusion series of 30 mg/kg and 10 mg/kg doses, respectively, were 16 mug/ml (95% CI: 10, 27) and 6 mug/ml (95% CI: 5, 9) levels, which neutralize a majority of circulating strains in vitro (50% inhibitory concentration [IC50] > 5 mug/ml). Post-infusion/injection serum VRC01 retained expected functional activity (virus neutralization, antibody-dependent cellular cytotoxicity, phagocytosis, and virion capture). The limitations of this study include the relatively small sample size of each VRC01 administration regimen and missing data from participants who were unable to complete all study visits.; CONCLUSIONS: VRC01 administered as either an IV infusion (10-40 mg/kg) given monthly or bimonthly, or as an SC injection (5 mg/kg) every 2 weeks, was found to be safe and well tolerated. In addition to maintaining drug concentrations consistent with neutralization of the majority of tested HIV strains, VRC01 concentrations from participants' sera were found to avidly capture HIV virions and to mediate antibody-dependent cellular phagocytosis, suggesting a range of anti-HIV immunological activities, warranting further clinical trials.; TRIAL REGISTRATION: Clinical Trials Registration: NCT02165267.=20
Laher, Fatima
Moodie, Zoe
Cohen, Kristen W.
Grunenberg, Nicole
Bekker, Linda-Gail
Allen, Mary
Frahm, Nicole
Yates, Nicole L.
Morris, Lynn
Malahleha, Mookho
Mngadi, Kathryn
Daniels, Brodie
Innes, Craig
Saunders, Kevin
Grant, Shannon
Yu, Chenchen
Gilbert, Peter B.
Phogat, Sanjay
DiazGranados, Carlos A.
Koutsoukos, Marguerite
Van Der Meeren, Olivier
Bentley, Carter
Mkhize, Nonhlanhla N.
Pensiero, Michael N.
Mehra, Vijay L.
Kublin, James G.
Corey, Lawrence
Montefiori, David C.
Gray, Glenda E.
McElrath, M. Juliana
Tomaras, Georgia D.
Pitisuttithum, Punnee
Awasthi, Sita
Mahairas, Gregory G
Shaw, Carolyn E
Huang, Meei-Li
Koelle, David M
Posavad, Christine
Corey, Lawrence
Friedman, Harvey M
UNLABELLED: We evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (gD2) to stimulate humoral immunity and UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and gD2 proteins were expressed in baculovirus, while the UL19 and UL47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing UL19 and UL47 stimulated human and murine CD4(+) and CD8(+) T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/gD2, with CpG and alum as adjuvants; (iii) immunized with the UL19/UL47 adenovirus vectors; or (iv) immunized with the combination of gC2/gD2-CpG/alum and the UL19/UL47 adenovirus vectors. Immunization with gC2/gD2 produced potent neutralizing antibodies, while UL19 and UL47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and UL19/UL47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/gD2-only group and none in the combined group developed acute disease. No animals in the gC2/gD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/gD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/gD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/gD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens UL19 and UL47 to the gC2/gD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/gD2 in the guinea pig model.; IMPORTANCE: HSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (gD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) would enhance the protection provided by the gC2/gD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/gD2 and UL19/UL47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs. Copyright =C2=A9 2015, American Society for Microbiology. All Rights Reserved.
Casper, Corey
Meier, Amalia S.
Wald, Anna
Morrow, Rhoda Ashley
Corey, Lawrence
Moscicki, Anna-Barbara
Objective: Human herpesvirus 8 (HHV-8) infection is common among children in areas where Kaposi sarcoma is endemic. Human herpesvirus 8 is uncommon in children but prevalent in adults at risk for human immunodeficiency virus (HIV) infection in the United States, including men who have sex with men (MSM) and women who engage in high-risk sexual behavior. We examined the prevalence and predictors of HHV-8 infection among adolescents with or at high risk for acquiring HIV infection. Design: Cross-sectional analysis. Setting: National study of HIV infection among adolescents in primary care. Participants: A total of 537 young adults practicing high-risk sexual behavior, of which 403 were women and 134 were men; among the 134 men, 75% were MSM. Interventions: Detailed questionnaires and testing for serum antibodies to HHV-8. Outcome Measure: Detection of serum antibodies to HHV-8. Results: Sixty (11.2%) of 537 young adults were HHV-8 seropositive, including 20 MSM (19.6%), 2 male heterosexuals (6.5%), and 27 female heterosexuals (8.2%). The prevalence of HHV-8 in HIV-positive MSM (17/74 [23.0%]) was twice as high as that in HIV-negative MSM (3/28 [10.7%]) (P=.18), but no characteristic predicted HHV-8 infection among MSM. In multivariate analysis, history of gonorrhea (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.4- 5.7; P <.01), history of having sex with women (OR, 2.4; 95% CI, 1.1-5.3; P=.03), and African American race (OR, 3.4; 95% CI, 1.1-10.0; P=.03) were associated with HHV-8 infection among women. Conclusions: Human herpesvirus 8 is common among US adolescents practicing high-risk sexual behaviors. Sexual identity, race, and sexual behavior may influence the risk of infection with HHV-8 in women.
Casper, Corey
Krantz, Elizabeth
Selke, Stacy
Kuntz, Steven R.
Wang, Jie
Huang, Meei-Li
Pauk, John S.
Corey, Lawrence
Wald, Anna
Background. Little is known about the clinical and virologic manifestations of human herpesvirus (HHV)-8 infection in immunocompetent persons in the absence of malignancy. Methods. A total of 46 human immunodeficiency virus-negative, HHV-8-seropositive men collected saliva daily, and 25 recorded 15 common symptoms daily (gastrointestinal, constitutional, and oropharyngeal) and absences from work or school. Quantitative polymerase chain reaction measured HHV-8 DNA in saliva. Results. Some 44 (96%) of 46 men reported having sex with men (MSM). Of the 44 MSM, 27 (61%) had HHV-8 detected in saliva on >= 1 day; heterosexual men also shed HHV-8. In analyses restricted to MSM, HHV-8 DNA was detected on 636 (22%) of 2897 days. Among MSM with HHV- 8 detected in saliva, the median rate was 20% (range, 1%-100%), with 30% shedding on > 50% of days, and the median quantity was 4.5 log(10) copies/ mL (range, 2.0-7.3 log(10) copies/mL). The quantity of HHV-8 shed was lower in nonwhites (P <.001) and younger participants (P = .03). The frequency of HHV-8 detection and quantity were correlated (r = 0.62; P < .001). Symptoms were reported on 10 (9%) of 114 days when HHV-8 was present, compared with 78 (9%) of 830 days without (odds ratio, 0.93 [95% confidence interval, 0.30-2.88]; P = .9). Conclusions. HHV-8 is detected frequently and intermittently in the saliva of chronically infected immunocompetent MSM, but this infection is asymptomatic.
Cattamanchi, Ashok
Saracino, Misty
Selke, Stacy
Huang, Meei-Li
Magaret, Amalia
Celum, Connie
Corey, Lawrence
Wald, Anna
Casper, Corey
Human herpesvirus-8 (HHV-8) replication is a key factor in Kaposi sarcoma, primary effusion lymphoma, and Castleman disease pathogenesis. In vitro data suggest that antivirals inhibit HHV-8 replication, but little data exist in humans. Daily oropharyngeal swabs were analyzed from HIV/HHV-8 dually infected men enrolled in three previous clinical trials of valecyclovir and famciclovir for HIV-1 and/or HSV-2 suppression. Fifty-eight participants contributed 6,036 swabs. HHV-8 was detected in 1,128 (19%) of 6,036 swabs, including 618 (21%) of 2,992 on placebo, 323 (15%) of 2,221 on valacyclovir, and 187 (23%) of 823 on famciclovir. After adjusting for baseline HIV viral load and highly active antiretroviral therapy (HAART) use, an 18% reduction in HHV-8 shedding frequency (IRR 0.822; P=0.011) was found in participants on valacyclovir and a 30% reduction (IRR 0.700; P<0.001) on famciclovir. HAART was associated with an 89% (IRR 0.129; P=0.048) reduction in HHV-8-shedding. Neither antiviral nor antiretroviral therapy was associated with decreased HHV-8 quantity. Valacyclovir and famciclovir were associated with modest but significant reductions in HHV-8 oropharyngeal shedding frequency. In contrast, HAART was a potent inhibitor of HHV-8 replication. Studies of whether antiviral therapy in combination with ART will prevent HHV-8-associated disease appear warranted. J. Med. Virol. 83:1696-1703, 2011. (C) 2011 Wiley-Liss, Inc.