Hassan AS, Esbjörnsson J, Wahome E, Thiong'o A, Makau GN, Price MA, Sanders EJ
HIV-1 subtype diversity, transmission networks and transmitted drug resistance amongst acute and early infected MSM populations from Coastal Kenya. PLoS ONE 2018;13(12):e0206177 doi: 10.1371/journal.pone.0206177
HIV-1 molecular epidemiology amongst men who have sex with men (MSM) in sub-Saharan Africa remains not well characterized. We aimed to determine HIV-1 subtype distribution, transmission clusters and transmitted drug resistance (TDR) in acute and early infected MSM from Coastal Kenya.
|
Namuniina A, Lutwama F, Biribawa VM, Kizza D, Kabuubi BR, Kitandwe PK, Mpendo J, Nanvubya A, Ssempiira J, Nalutaaya A, Ssetaala A, Welsh S, Price MA, Kiwanuka N, Bagaya BS
Field performance of PIMA Point-of-Care Machine for CD4 Enumeration Under a Mobile HIV Counseling and Testing Program in Remote Fishing Communities of Lake Victoria, Uganda. AIDS Res. Hum. Retroviruses 2018; doi: 10.1089/AID.2018.0223
Uganda is among the most HIV/AIDS afflicted countries, and many HIV infected persons live in remote areas with poor access to healthcare. The success of HIV care programs relies in part on patient monitoring using CD4 T cell counts. We conducted an evaluation of the point-of-care PIMA test using BD FACSCount as a gold standard.
Keywords: Fishing Communities
|
Pauthner MG, Nkolola JP, Havenar-Daughton C, Murrell B, Reiss SM, Bastidas R, Prévost J, Nedellec R, von Bredow B, Abbink P, Cottrell CA, Kulp DW, Tokatlian T, Nogal B, Bianchi M, Li H, Lee JH, Butera ST, Evans DT, Hangartner L, Finzi A, Wilson IA, Wyatt RT, Irvine DJ, Schief WR, Ward AB, Sanders RW, Crotty S, Shaw GM, Barouch DH, Burton DR
Vaccine-Induced Protection from Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers. Immunity 2019; doi: S1074-7613(18)30493-X
Passive administration of HIV neutralizing antibodies (nAbs) can protect macaques from hard-to-neutralize (tier 2) chimeric simian-human immunodeficiency virus (SHIV) challenge. However, conditions for nAb-mediated protection after vaccination have not been established. Here, we selected groups of 6 rhesus macaques with either high or low serum nAb titers from a total of 78 animals immunized with recombinant native-like (SOSIP) Env trimers. Repeat intrarectal challenge with homologous tier 2 SHIV led to rapid infection in unimmunized and low-titer animals. High-titer animals, however, demonstrated protection that was gradually lost as nAb titers waned over time. An autologous serum ID nAb titer of ∼1:500 afforded more than 90% protection from medium-dose SHIV infection. In contrast, antibody-dependent cellular cytotoxicity and T cell activity did not correlate with protection. Therefore, Env protein-based vaccination strategies can protect against hard-to-neutralize SHIV challenge in rhesus macaques by inducing tier 2 nAbs, provided appropriate neutralizing titers can be reached and maintained.
Topics: HIV Immunogen Design
|
Martins MA, Gonzalez-Nieto L, Shin YC, Domingues A, Gutman MJ, Maxwell HS, Magnani DM, Ricciardi MJ, Pedreño-Lopez N, Bailey VK, Altman JD, Parks CL, Allison DB, Ejima K, Rakasz EG, Capuano S, Desrosiers RC, Lifson JD, Watkins DI
The Frequency or vaccine-induced T-cell responses do not predict the rate of acquisition after repeated intrarectal SIVmac239 challenges in rhesus macaques. J. Virol. 2019; 93(5). pii: e01626-18. doi: JVI.01626-18
Approximately 50% of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) allele spontaneously control chronic phase viremia after infection with the pathogenic simian immunodeficiency virus (SIV)mac239 clone. CD8+ T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infected RMs. Here we evaluated if robust vaccine-elicited CD8+ T-cell responses against Vif and Nef can prevent systemic infection in RMs following mucosal SIV challenges. Ten RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8+ T-cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsies. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges and three of them remained aviremic after 3-4 additional challenges. The rate of SIV acquisition in vaccinees was numerically lower (albeit not statistically significant) than that of controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection versus those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection. It is generally accepted that the antiviral effects of vaccine-induced classical CD8+ T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a slower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class-I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8+ T-cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection.
Topics: HIV Immunogen Design
|
Ogunshola F, Anmole G, Miller RL, Goering E, Nkosi T, Muema D, Mann J, Ismail N, Chopera D, Ndung'u T, Brockman MA, Ndhlovu ZM
Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants. Nat Commun 2018;9(1):5023 doi: 10.1038/s41467-018-07209-7
Some closely related human leukocyte antigen (HLA) alleles are associated with variable clinical outcomes following HIV-1 infection despite presenting the same viral epitopes. Mechanisms underlying these differences remain unclear but may be due to intrinsic characteristics of the HLA alleles or responding T cell repertoires. Here we examine CD8 T cell responses against the immunodominant HIV-1 Gag epitope TL9 (TPQDLNTML) in the context of the protective allele B*81:01 and the less protective allele B*42:01. We observe a population of dual-reactive T cells that recognize TL9 presented by both B*81:01 and B*42:01 in individuals lacking one allele. The presence of dual-reactive T cells is associated with lower plasma viremia, suggesting a clinical benefit. In B*42:01 expressing individuals, the dual-reactive phenotype defines public T cell receptor (TCR) clones that recognize a wider range of TL9 escape variants, consistent with enhanced control of viral infection through containment of HIV-1 sequence adaptation.
|
Masyuko S, Mukui I, Njathi O, Kimani M, Oluoch P, Wamicwe J, Mutegi J, Njogo S, Anyona M, Muchiri P, Maikweki L, Musyoki H, Bahati P, Kyongo J, Marwa T, Irungu E, Kiragu M, Kioko U, Ogando J, Were D, Bartilol K, Sirengo M, Mugo N, Baeten JM, Cherutich P, PrEP Technical Working Group OBOT
Pre-exposure prophylaxis rollout in a national public sector program: the Kenyan case study. Sex Health 2018;15(6):578-586 doi: 10.1071/SH18090
Background While advances have been made in HIV prevention and treatment, new HIV infections continue to occur. The introduction of pre-exposure prophylaxis (PrEP) as an additional HIV prevention option for those at high risk of HIV may change the landscape of the HIV epidemic, especially in sub-Saharan Africa, which bears the greatest HIV burden.
|
Kiwanuka N, Mpendo J, Asiimwe S, Ssempiira J, Nalutaaya A, Nambuusi B, Wambuzi M, Kabuubi B, Namuniina A, Oporia F, Nanvubya A, Ssetaala A
A randomized trial to assess retention rates using mobile phone reminders versus physical contact tracing in a potential HIV vaccine efficacy population of fishing communities around Lake Victoria, Uganda. BMC Infect. Dis. 2018;18(1):591 doi: 10.1186/s12879-018-3475-0
High retention (follow-up) rates improve the validity and statistical power of outcomes in longitudinal studies and the effectiveness of programs with prolonged administration of interventions. We assessed participant retention in a potential HIV vaccine trials population of fishing communities along Lake Victoria, Uganda.
Topics: HIV Epidemiology
Keywords: Fishing Communities
|
He L, Kumar S, Allen JD, Huang D, Lin X, Mann CJ, Saye-Francisco KL, Copps J, Sarkar A, Blizard GS, Ozorowski G, Sok D, Crispin M, Ward AB, Nemazee D, Burton DR, Wilson IA, Zhu J
HIV-1 vaccine design through minimizing envelope metastability. Sci Adv 2018;4(11):eaau6769 doi: 10.1126/sciadv.aau6769
Overcoming envelope metastability is crucial to trimer-based HIV-1 vaccine design. Here, we present a coherent vaccine strategy by minimizing metastability. For 10 strains across five clades, we demonstrate that the gp41 ectodomain (gp41) is the main source of envelope metastability by replacing wild-type gp41 with BG505 gp41 of the uncleaved prefusion-optimized (UFO) design. These gp41-swapped trimers can be produced in CHO cells with high yield and high purity. The crystal structure of a gp41-swapped trimer elucidates how a neutralization-resistant tier 3 virus evades antibody recognition of the V2 apex. UFO trimers of transmitted/founder viruses and UFO trimers containing a consensus-based ancestral gp41 suggest an evolutionary root of metastability. The gp41-stabilized trimers can be readily displayed on 24- and 60-meric nanoparticles, with incorporation of additional T cell help illustrated for a hyperstable 60-mer, I3-01. In mice and rabbits, these gp140 nanoparticles induced tier 2 neutralizing antibody responses more effectively than soluble trimers.
Topics: HIV Immunogen Design
|
Nyasani DK, Mutua GN, Sajabi RM, Ng'ang'a JW, Gachie JN, Maina AM, Lusike LL, Anzala AO, Price MA, Manyonyi GO
Reported willingness to participate in a hypothetical HIV vaccine trial and its translation to actual participation among healthy adults-Experience from Kenya. PLoS ONE 2018;13(11):e0206656 doi: 10.1371/journal.pone.0206656
To evaluate initial reported willingness to participate in a hypothetical HIV vaccine clinical trial and actual participation of volunteers in a longitudinal observational study.
Topics: Capacity Building and Research Preparedness
|
Tokatlian T, Kulp DW, Mutafyan AA, Jones CA, Menis S, Georgeson E, Kubitz M, Zhang MH, Melo MB, Silva M, Yun DS, Schief WR, Irvine DJ
Enhancing Humoral Responses Against HIV Envelope Trimers via Nanoparticle Delivery with Stabilized Synthetic Liposomes. Sci Rep 2018;8(1):16527 doi: 10.1038/s41598-018-34853-2
An HIV vaccine capable of eliciting durable neutralizing antibody responses continues to be an important unmet need. Multivalent nanoparticles displaying a high density of envelope trimers may be promising immunogen forms to elicit strong and durable humoral responses to HIV, but critical particle design criteria remain to be fully defined. To this end, we developed strategies to covalently anchor a stabilized gp140 trimer, BG505 MD39, on the surfaces of synthetic liposomes to study the effects of trimer density and vesicle stability on vaccine-elicited humoral responses in mice. CryoEM imaging revealed homogeneously distributed and oriented MD39 on the surface of liposomes irrespective of particle size, lipid composition, and conjugation strategy. Immunization with covalent MD39-coupled liposomes led to increased germinal center and antigen-specific T follicular helper cell responses and significantly higher avidity serum MD39-specific IgG responses compared to immunization with soluble MD39 trimers. A priming immunization with liposomal-MD39 was important for elicitation of high avidity antibody responses, regardless of whether booster immunizations were administered with either soluble or particulate trimers. The stability of trimer anchoring to liposomes was critical for these effects, as germinal center and output antibody responses were further increased by liposome compositions incorporating sphingomyelin that exhibited high in vitro stability in the presence of serum. Together these data highlight key liposome design features for optimizing humoral immunity to lipid nanoparticle immunogens.
Topics: HIV Immunogen Design
|