Global and Regional Estimates for Subtype-Specific Therapeutic and Prophylactic HIV-1 Vaccines: A Modeling Study

Global HIV-1 genetic diversity forms a major obstacle to the development of an HIV vaccine. It may be necessary to employ subtype-specific HIV-1 vaccines in individual countries according to their HIV-1 subtype distribution. We estimated the global and regional need for subtype-specific HIV-1 vaccines. We took into account the proportions of different HIV-1 variants circulating in each country, the genetic composition of HIV-1 recombinants, and the different genome segments (gag, pol, env) that may be incorporated into vaccines. We modeled different scenarios according to whether countries would employ subtype-specific HIV-1 vaccines against (1) the most common subtype; (2) subtypes contributing more than 5% of HIV infections; or (3) all circulating subtypes. For therapeutic vaccines targeting the most common HIV-1 subtype in each country, 16.5 million doses of subtype C vaccine were estimated globally, followed by subtypes A (14.3 million) and B (4.2 million). A vaccine based on env required 2.6 million subtype E doses, and a vaccine based on pol required 4.8 million subtype G doses. For prophylactic vaccines targeting the most common HIV-1 subtype in each country, 1.9 billion doses of subtype A vaccine were estimated globally, followed by subtype C (1.1 billion) and subtype B (1.0 billion). A vaccine based on env required 1.2 billion subtype E doses, and a vaccine based on pol required 0.3 billion subtype G doses. If subtype-specific HIV-1 vaccines are also directed against less common subtypes in each country, vaccines targeting subtypes D, F, H, and K are also needed and would require up to five times more vaccine doses in total. We conclude that to provide global coverage, subtype-specific HIV-1 vaccines need to be directed against subtypes A, B, and C. Vaccines targeting env also need to include subtype E and those targeting pol need to include subtype G.

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Efficiencies of Four Versions of the AMPLICOR HIV-1 MONITOR Test for Quantification of Different Subtypes of Human Immunodeficiency Virus Type 1

Journal of Clinical Microbiology ◽

10.1128/jcm.37.1.110-116.1999 ◽

1999 ◽

Vol 37 (1) ◽

pp. 110-116 ◽

Cited By ~ 74

Author(s):

K. Triques ◽

J. Coste ◽

J. L. Perret ◽

C. Segarra ◽

E. Mpoudi ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Viral Load ◽

Pcr Primers ◽

Load Test ◽

Subtype C ◽

Subtype B ◽

Immunodeficiency Virus ◽

Subtype A ◽

Hiv 1

Three versions of a commercial human immunodeficiency virus (HIV) type 1 (HIV-1) load test (the AMPLICOR HIV-1 MONITOR Test versions 1.0, 1.0+, and 1.5; Roche Diagnostics, Branchburg, N.J.) were evaluated for their ability to detect and quantify HIV-1 RNA of different genetic subtypes. Plasma samples from 96 patients infected with various subtypes of HIV-1 (55 patients infected with subtype A, 9 with subtype B, 21 with subtype C, 2 with subtype D, 7 with subtype E, and 2 with subtype G) and cultured virus from 29 HIV-1 reference strains (3 of subtype A, 6 of subtype B, 5 of subtype C, 3 of subtype D, 8 of subtype E, 3 of subtype F, and 1 of subtype G) were tested. Detection of subtypes A and E was significantly improved with versions 1.0+ and 1.5 compared to that with version 1.0, whereas detection of subtypes B, C, D, and G was equivalent with the three versions. Versions 1.0, 1.0+, and 1.5 detected 65, 98, and 100% of the subtype A-infected samples from patients, respectively, and 71, 100, and 100% of the subtype E-infected samples from patients, respectively. Version 1.5 yielded a significant increase in viral load for samples infected with subtypes A and E (greater than 1 log10 HIV RNA copies/ml). For samples infected with subtype B, C, and D and tested with version 1.5, only a slight increase in viral load was observed (<0.5 log10). We also evaluated a prototype automated version of the test that uses the same PCR primers as version 1.5. The results with the prototype automated test were highly correlated with those of the version 1.5 test for all subtypes, but were lower overall. The AMPLICOR HIV-1 MONITOR Test, version 1.5, yielded accurate measurement of the HIV load for all HIV-1 subtypes tested, which should allow the test to be used to assess disease prognosis and response to antiretroviral treatment in patients infected with a group M HIV-1 subtype.

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Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers

Journal of Virology ◽

10.1128/jvi.02652-15 ◽

2015 ◽

Vol 90 (6) ◽

pp. 2806-2817 ◽

Cited By ~ 69

Author(s):

Javier Guenaga ◽

Viktoriya Dubrovskaya ◽

Natalia de Val ◽

Shailendra K. Sharma ◽

Barbara Carrette ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Small Animal ◽

Subtype C ◽

Disulfide Linkage ◽

Vaccine Candidates ◽

Subtype B ◽

Subtype A ◽

Induced Changes ◽

Hiv 1 ◽

Hiv Diversity

ABSTRACTDue to high viral diversity, an effective HIV-1 vaccine will likely require Envs derived from multiple subtypes to generate broadly neutralizing antibodies (bNAbs). Soluble Env mimics, like the native flexibly linked (NFL) and SOSIP trimers, derived from the subtype A BG505 Env, form homogeneous, stable native-like trimers. However, other Env sequences, such as JRFL and 16055 from subtypes B and C, do so to a lesser degree. The high-resolution BG505 SOSIP crystal structures permit the identification and redesign of Env elements involved in trimer stability. Here, we identified structure trimer-derived (TD) residues that increased the propensity of the subtype B JRFL and subtype C 16055 Env sequences to form well-ordered, homogenous, and highly stable soluble trimers. The generation of these spike mimics no longer required antibody-based selection, positive or negative. Using the redesigned subtype B and C trimer representatives as respective foundations, we further stabilized the NFL TD trimers by engineering an intraprotomer disulfide linkage in the prebridging sheet, I201C-A433C (CC), that locks the gp120 in the receptor nontriggered state. We demonstrated that this disulfide pair prevented CD4 induced-conformational rearrangements in NFL trimers derived from the prototypic subtype A, B, and C representatives. Coupling the TD-based design with the engineered disulfide linkage, CC, increased the propensity of Env to form soluble highly stable spike mimics that are resistant to CD4-induced changes. These advances will allow testing of the hypothesis that such stabilized immunogens will more efficiently elicit neutralizing antibodies in small-animal models and primates.IMPORTANCEHIV-1 displays unprecedented global diversity circulating in the human population. Since the envelope glycoprotein (Env) is the target of neutralizing antibodies, Env-based vaccine candidates that address such diversity are needed. Soluble well-ordered Env mimics, typified by NFL and SOSIP trimers, are attractive vaccine candidates. However, the current designs do not allow most Envs to form well-ordered trimers. Here, we made design modifications to increase the propensity of representatives from two of the major HIV subtypes to form highly stable trimers. This approach should be applicable to other viral Envs, permitting the generation of a repertoire of homogeneous, highly stable trimers. The availability of such an array will allow us to assess if sequential or cocktail immune strategies can overcome some of the vaccine challenges presented by HIV diversity.

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Genomic diversity of human immunodeficiency virus type-1 in India

International Journal of STD & AIDS ◽

10.1258/0956462021924749 ◽

2002 ◽

Vol 13 (2) ◽

pp. 115-118 ◽

Cited By ~ 36

Author(s):

A K Sahni ◽

V V S P Prasad ◽

P Seth

Keyword(s):

Genomic Diversity ◽

New Delhi ◽

Subtype C ◽

Medical Sciences ◽

Clear Cut ◽

Reference Centre ◽

Subtype B ◽

History Of ◽

Subtype A ◽

Hiv 1

Surveillance of HIV-1 subtypes has important implications for the development of candidate vaccine and understanding the possible differences in the transmission and natural history of different subtypes. In this study, HIV-1 subtypes were determined for homologies in the C2-V3-V5 region by heteroduplex mobility assay (HMA) in HIV-1 seropositive patients referred to the National HIV/AIDS Reference Centre, All India Institute of Medical Sciences in New Delhi, India. Of the 125 samples analysed, 98 (78.4%) were HIV-1 subtype C, 11 (8.8%) were subtype B′, 3 (2.4%) were subtype A and 2 (1.6%) were subtype E. In 11 samples, subtype determination was not clear-cut. It is possible that these individuals may be infected with recombinant strains of HIV-1. These findings may have significant implications for the designing and testing of effective HIV-1 vaccine candidate in India.

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The influence of the expanding HIV genetic diversity on molecular diagnosis in the Philippines

International Journal of STD & AIDS ◽

10.1258/095646203321156908 ◽

2003 ◽

Vol 14 (2) ◽

pp. 125-131 ◽

Cited By ~ 4

Author(s):

A Espantaleon ◽

S Kageyama ◽

M T Bernardo ◽

T Nakano ◽

P S Leaño ◽

...

Keyword(s):

Genetic Diversity ◽

Molecular Diagnosis ◽

The Philippines ◽

Rapid Expansion ◽

Subtype C ◽

Universal Primer ◽

Subtype B ◽

Pcr Product ◽

Subtype A ◽

Hiv 1

Since the discovery in the Philippines of the first AIDS case in 1984, several subtypes of HIV-1 have been discovered. From the persons diagnosed in the early 1980s only subtype B was found and thereafter other subtypes, C, D, E, and F were also identified although HIV was not particularly prevalent at that time. In this paper, we determine whether the rapid expansion of genetic diversity will influence molecular diagnosis by polymerase chain reaction (PCR). First, we determine HIV-1 subtype on env (V3) and gag (p24) gene as a means of rapid genetic diversity. Secondly, we tried to analyse and identify homologous regions of gag (p24) gene of HIV genome for diagnostic purposes of designing primers. Out of 46 samples analysed, six subtypes were classified based on gag and env gene subtyping namely: 33 subtype B/B (71.2%), nine subtype A/E and one each subtype C/C, A/B and G/A (2.2% each). As a result, occurrence of non-subtype B and inter-subtype recombinant contributed to expanding genetic diversity. Based on inter- and intra-subtype gag alignment, oligonucleotides (>10 bases in length) could be easily selected as a universal primer to produce the PCR product composed of more than 100bp. This indicates that the PCR technology can be safely used with limited length of primers for the diagnosis of HIV infection in this country.

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Distinct Mutation Pathways of Non-Subtype B HIV-1 during In Vitro Resistance Selection with Nonnucleoside Reverse Transcriptase Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00829-10 ◽

2010 ◽

Vol 54 (11) ◽

pp. 4812-4824 ◽

Cited By ~ 31

Author(s):

Ming-Tain Lai ◽

Meiqing Lu ◽

Peter J. Felock ◽

Renee C. Hrin ◽

Ying-Jie Wang ◽

...

Keyword(s):

Cell Culture ◽

Reverse Transcriptase ◽

Subtype C ◽

Reverse Transcriptase Inhibitors ◽

Resistance Selection ◽

Nonnucleoside Reverse Transcriptase Inhibitors ◽

Subtype B ◽

Subtype A ◽

Hiv 1

ABSTRACT Studies were conducted to investigate mutation pathways among subtypes A, B, and C of human immunodeficiency virus type 1 (HIV-1) during resistance selection with nonnucleoside reverse transcriptase inhibitors (NNRTIs) in cell culture under low-multiplicity of infection (MOI) conditions. The results showed that distinct pathways were selected by different virus subtypes under increasing selective pressure of NNRTIs. F227C and Y181C were the major mutations selected by MK-4965 in subtype A and C viruses during resistance selection. With efavirenz (EFV), F227C and V106M were the major mutations responsible for viral breakthrough in subtype A viruses, whereas a single pathway (G190A/V106M) accounted for mutation development in subtype C viruses. Y181C was the dominant mutation in the resistance selection with etravirine (ETV) in subtype A, and E138K/H221Y were the mutations detected in the breakthrough viruses from subtype C viruses with ETV. In subtype B viruses, on the other hand, known NNRTI-associated mutations (e.g., Y181C, P236L, L100I, V179D, and K103N) were selected by the NNRTIs. The susceptibility of the subtype A and B mutant viruses to NNRTIs was determined in order to gain insight into the potential mechanisms of mutation development. Collectively, these results suggest that minor differences may exist in conformation of the residues within the NNRTI binding pocket (NNRTIBP) of reverse transcriptase (RT) among the three subtypes of viruses. Thus, the interactions between NNRTIs and the residues in the NNRTIBPs of different subtypes may not be identical, leading to distinct mutation pathways during resistance selection in cell culture.

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Nationwide Study of Drug Resistance Mutations in HIV-1 Infected Individuals under Antiretroviral Therapy in Brazil

International Journal of Molecular Sciences ◽

10.3390/ijms22105304 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5304

Author(s):

Ana Santos-Pereira ◽

Vera Triunfante ◽

Pedro M. M. Araújo ◽

Joana Martins ◽

Helena Soares ◽

...

Keyword(s):

Drug Resistance ◽

People Living With Hiv ◽

Resistance Mutations ◽

Subtype C ◽

Viral Loads ◽

Drug Resistance Mutations ◽

Subtype B ◽

Low Prevalence ◽

Living With Hiv ◽

Hiv 1

The success of antiretroviral treatment (ART) is threatened by the emergence of drug resistance mutations (DRM). Since Brazil presents the largest number of people living with HIV (PLWH) in South America we aimed at understanding the dynamics of DRM in this country. We analyzed a total of 20,226 HIV-1 sequences collected from PLWH undergoing ART between 2008–2017. Results show a mild decline of DRM over the years but an increase of the K65R reverse transcriptase mutation from 2.23% to 12.11%. This increase gradually occurred following alterations in the ART regimens replacing zidovudine (AZT) with tenofovir (TDF). PLWH harboring the K65R had significantly higher viral loads than those without this mutation (p < 0.001). Among the two most prevalent HIV-1 subtypes (B and C) there was a significant (p < 0.001) association of K65R with subtype C (11.26%) when compared with subtype B (9.27%). Nonetheless, evidence for K65R transmission in Brazil was found both for C and B subtypes. Additionally, artificial neural network-based immunoinformatic predictions suggest that K65R could enhance viral recognition by HLA-B27 that has relatively low prevalence in the Brazilian population. Overall, the results suggest that tenofovir-based regimens need to be carefully monitored particularly in settings with subtype C and specific HLA profiles.

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CCR5- and CXCR4-Tropic Subtype C Human Immunodeficiency Virus Type 1 Isolates Have a Lower Level of Pathogenic Fitness than Other Dominant Group M Subtypes: Implications for the Epidemic

Journal of Virology ◽

10.1128/jvi.02051-08 ◽

2009 ◽

Vol 83 (11) ◽

pp. 5592-5605 ◽

Cited By ~ 63

Author(s):

Awet Abraha ◽

Immaculate L. Nankya ◽

Richard Gibson ◽

Korey Demers ◽

Denis M. Tebit ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Ex Vivo ◽

Sub Saharan Africa ◽

Subtype C ◽

Immunodeficiency Virus ◽

Subtype A ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) subtype C is the dominant subtype globally, due largely to the incidence of subtype C infections in sub-Saharan Africa and east Asia. We compared the relative replicative fitness (ex vivo) of the major (M) group of HIV-1 subtypes A, B, C, D, and CRF01_AE and group O isolates. To estimate pathogenic fitness, pairwise competitions were performed between CCR5-tropic (R5) or CXCR4-tropic (X4) virus isolates in peripheral blood mononuclear cells (PBMC). A general fitness order was observed among 33 HIV-1 isolates; subtype B and D HIV-1 isolates were slightly more fit than the subtype A and dramatically more fit than the 12 subtype C isolates. All group M isolates were more fit (ex vivo) than the group O isolates. To estimate ex vivo transmission fitness, a subset of primary HIV-1 isolates were examined in primary human explants from penile, cervical, and rectal tissues. Only R5 isolates and no X4 HIV-1 isolates could replicate in these tissues, whereas the spread to PM1 cells was dependent on active replication and passive virus transfer. In tissue competition experiments, subtype C isolates could compete with and, in some cases, even win over subtype A and D isolates. However, when the migratory cells from infected tissues were mixed with a susceptible cell line, the subtype C isolates were outcompeted by other subtypes, as observed in experiments with PBMC. These findings suggest that subtype C HIV-1 isolates might have equal transmission fitness but reduced pathogenic fitness relative to other group M HIV-1 isolates.

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Genetic diversity and primary resistance among HIV-1-positive patients from Maringá, Paraná, Brazil

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652012000400005 ◽

2012 ◽

Vol 54 (4) ◽

pp. 207-213 ◽

Cited By ~ 8

Author(s):

Karine Vieira Gaspareto ◽

Flávia Myrian Martins de Almeida Mello ◽

José Ricardo Colleti Dias ◽

Vera Alice Fernandes Meneguetti ◽

Marta Evelyn Giansante Storti ◽

...

Keyword(s):

Specific Antigen ◽

Resistance Mutation ◽

Drug Resistance Mutation ◽

Subtype C ◽

Primary Resistance ◽

Subtype B ◽

Pcr Products ◽

Treatment Naïve ◽

Positive Treatment ◽

Hiv 1

The objective of this study is to identify subtypes of Human Immunodeficiency Virus type 1 (HIV-1) and to analyze the presence of mutations associated to antiretroviral resistance in the protease (PR) and reverse transcriptase (RT) regions from 48 HIV-1 positive treatment naïve patients from an outpatient clinic in Maringá, Paraná, Brazil. Sequencing was conducted using PR, partial RT and group-specific antigen gene (gag) nested PCR products from retrotranscribed RNA. Transmitted resistance was determined according to the Surveillance Drug Resistance Mutation List (SDRM) algorithm. Phylogenetic and SimPlot analysis of concatenated genetic segments classified sequences as subtype B 19/48 (39.6%), subtype C 12/48 (25%), subtype F 4/48 (8.3%), with 13/48 (27.1%) recombinant forms. Most recombinant forms were B mosaics (B/F 12.5%, B/C 10.4%), with one C/F (2.1%) and one complex B/C/F mosaic (2.1%). Low levels of transmitted resistance were found in this study, 2/48 (2.1% to NRTIs and 2.1% for PI). This preliminary data may subsidize the monitoring of the HIV evolution in the region.

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Reconstructing the Dissemination Dynamics of the Major HIV-1 Subtype B Non-Pandemic Lineage Circulating in Brazil

Viruses ◽

10.3390/v11100909 ◽

2019 ◽

Vol 11 (10) ◽

pp. 909

Author(s):

Ighor Arantes ◽

Myuki Alfaia Esashika Crispim ◽

Mônica Nogueira da Guarda Reis ◽

Mariane Martins Araújo Stefani ◽

Gonzalo Bello

Keyword(s):

Hiv Infections ◽

Spreading Rate ◽

South American ◽

Caribbean Islands ◽

Subtype B ◽

Demographic Dynamics ◽

Immunodeficiency Virus ◽

Northern Brazil ◽

Hiv 1

Non-pandemic variants of the Human Immunodeficiency Virus Type 1 (HIV-1) subtype B accounts for a significant fraction of HIV infections in several Caribbean islands, Northeastern South American countries and the Northern Brazilian states of Roraima and Amazonas. In this paper, we used a comprehensive dataset of HIV-1 subtype B pol sequences sampled in Amazonas and Roraima between 2007 and 2017 to reconstruct the phylogeographic and demographic dynamics of the major HIV-1 subtype B non-pandemic Brazilian lineage, designated as BCAR-BR-I. Our analyses revealed that its origin could be traced to one of many viral introductions from French Guiana and Guyana into Northern Brazil, which probably occurred in the state of Amazonas around the late 1970s. The BCAR-BR-I clade was rapidly disseminated from Amazonas to Roraima, and the epidemic grew exponentially in these Northern Brazilian states during the 1980s and 1990s, coinciding with a period of economic and fast population growth in the region. The spreading rate of the BCAR-BR-I clade, however, seems to have slowed down since the early 2000s, despite the continued expansion of the HIV-1 epidemic in this region in the last decade.

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