Massive Iatrogenic Outbreak of Human Immunodeficiency Virus Type 1 in Rural Cambodia, 2014–2015

Abstract Background In 2014–2015, 242 individuals aged 2–89 years were newly diagnosed with human immunodeficiency virus type 1 (HIV-1) in Roka, a rural commune in Cambodia. A case-control study attributed the outbreak to unsafe injections. We aimed to reconstruct the likely transmission history of the outbreak. Methods We assessed in 209 (86.4%) HIV-infected cases the presence of hepatitis C virus (HCV) and hepatitis B virus (HBV). We identified recent infections using antibody (Ab) avidity testing for HIV and HCV. We performed amplification, sequencing, and evolutionary phylogenetic analyses of viral strains. Geographical coordinates and parenteral exposure through medical services provided by an unlicensed healthcare practitioner were obtained from 193 cases and 1499 controls during interviews. Results Cases were coinfected with HCV (78.5%) and HBV (12.9%). We identified 79 (37.8%) recent (<130 days) HIV infections. Phylogeny of 202 HIV env C2V3 sequences showed a 198-sample CRF01_AE strains cluster, with time to most recent common ancestor (tMRCA) in September 2013 (95% highest posterior density, August 2012–July 2014), and a peak of 15 infections/day in September 2014. Three geospatial HIV hotspots were discernible in Roka and correlated with high exposure to the practitioner (P = .04). Fifty-nine of 153 (38.6%) tested cases showed recent (<180 days) HCV infections. Ninety HCV NS5B sequences formed 3 main clades, 1 containing 34 subtypes 1b with tMRCA in 2012, and 2 with 51 subtypes 6e and tMRCAs in 2002–2003. Conclusions Unsafe injections in Cambodia most likely led to an explosive iatrogenic spreading of HIV, associated with a long-standing and more genetically diverse HCV propagation.

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Evolutionary Indicators of Human Immunodeficiency Virus Type 1 Reservoirs and Compartments

Journal of Virology ◽

10.1128/jvi.77.9.5540-5546.2003 ◽

2003 ◽

Vol 77 (9) ◽

pp. 5540-5546 ◽

Cited By ~ 82

Author(s):

David C. Nickle ◽

Mark A. Jensen ◽

Daniel Shriner ◽

Scott J. Brodie ◽

Lisa M. Frenkel ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Strong Predictor ◽

Cell Types ◽

Recent Common Ancestor ◽

Latent Reservoir ◽

Most Recent Common Ancestor ◽

Immunodeficiency Virus

ABSTRACT In vivo virologic compartments are cell types or tissues between which there is a restriction of virus flow, while virologic reservoirs are cell types or tissues in which there is a relative restriction of replication. The distinction between reservoirs and compartments is important because therapies that would be effective against a reservoir may not be effective against viruses produced by a given compartment, and vice versa. For example, the use of cytokines to “flush out” long-lived infected cells in patients on highly active antiretroviral therapy (T. W. Chun, D. Engel, M. M. Berrey, T. Shea, L. Corey, and A. S. Fauci, Proc. Natl. Acad. Sci. USA 95:8869-8873, 1998) may be successful for a latent reservoir but may not impact a compartment in which virus continues to replicate because of poor drug penetration. Here, we suggest phylogenetic criteria to illustrate, define, and differentiate between reservoirs and compartments. We then apply these criteria to the analysis of simulated and actual human immunodeficiency virus type 1 sequence data sets. We report that existing statistical methods work quite well at detecting viral compartments, and we learn from simulations that viral divergence from a calculated most recent common ancestor is a strong predictor of viral reservoirs.

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Timing and Reconstruction of the Most Recent Common Ancestor of the Subtype C Clade of Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.78.19.10501-10506.2004 ◽

2004 ◽

Vol 78 (19) ◽

pp. 10501-10506 ◽

Cited By ~ 26

Author(s):

Simon A. A. Travers ◽

Jonathan P. Clewley ◽

Judith R. Glynn ◽

Paul E. M. Fine ◽

Amelia C. Crampin ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Common Ancestor ◽

Recent Common Ancestor ◽

Subtype C ◽

Most Recent Common Ancestor ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) subtype C is responsible for more than 55% of HIV-1 infections worldwide. When this subtype first emerged is unknown. We have analyzed all available gag (p17 and p24) and env (C2-V3) subtype C sequences with known sampling dates, which ranged from 1983 to 2000. The majority of these sequences come from the Karonga District in Malawi and include some of the earliest known subtype C sequences. Linear regression analyses of sequence divergence estimates (with four different approaches) were plotted against sample year to estimate the year in which there was zero divergence from the reconstructed ancestral sequence. Here we suggest that the most recent common ancestor of subtype C appeared in the mid- to late 1960s. Sensitivity analyses, by which possible biases due to oversampling from one district were explored, gave very similar estimates.

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Comparisons of Human Immunodeficiency Virus Type 1 Envelope Variants in Blood and Genital Fluids near the Time of Male-to-Female Transmission

Journal of Virology ◽

10.1128/jvi.01769-18 ◽

2019 ◽

Vol 93 (13) ◽

Cited By ~ 1

Author(s):

Corey A. Williams-Wietzikoski ◽

Mary S. Campbell ◽

Rachel Payant ◽

Airin Lam ◽

Hong Zhao ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Genital Tract ◽

Recent Common Ancestor ◽

Female Partners ◽

Immunodeficiency Virus ◽

Male To Female ◽

Hiv 1

ABSTRACTTo better understand the transmission of human immunodeficiency virus type 1 (HIV-1), the genetic characteristics of blood and genital viruses from males were compared to those of the imputed founding virus population in their female partners. Initially serodiscordant heterosexual African couples with sequence-confirmed male-to-female HIV-1 transmission and blood and genital specimens collected near the time of transmission were studied. Single viral templates from blood plasma and genital tract RNA and DNA were sequenced across HIV-1envgp160. Eight of 29 couples examined yielded viral sequences from both tissues. Analysis of these couples’ sequences demonstrated, with one exception, that the women’s founding viral populations arose from a single viral variant and were CCR5 tropic, even though CXCR4 variants were detected within four males. The median genetic distance of the imputed most recent common ancestor of the women’s founder viruses showed that they were closer to the semen viruses than to the blood viruses of their transmitting male partner, but this finding was biased by detection of a greater number of viral clades in the blood. Using multiple assays, the blood and genital viruses were consistently found to be compartmentalized in only two of eight men. No distinct amino acid signatures in the men’s viruses were found to link to the women’s founders, nor did the women’senvsequences have shorter variable loops or fewer N-linked glycosylation sites. The lack of selective factors, except for coreceptor tropism, is consistent with others’ findings in male-to-female and high-risk transmissions. The infrequent compartmentalization between the transmitters’ blood and semen viruses suggests that cell-free blood virus likely includes HIV-1 sequences representative of those of viruses in semen.IMPORTANCEMucosal transmissions account for the majority of HIV-1 infections. Identification of the viral characteristics associated with transmission would facilitate vaccine design. This study of HIV strains from transmitting males and their seroconverting female partners found that the males’ genital tract viruses were rarely distinct from the blood variants. The imputed founder viruses in women were genetically similar to both the blood and genital tract variants of their male partners, indicating a lack of evidence for genital tract-specific lineages. These findings suggest that targeting vaccine responses to variants found in blood are likely to also protect from genital tract variants.

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Reconstruction and Function of Ancestral Center-of-Tree Human Immunodeficiency Virus Type 1 Proteins

Journal of Virology ◽

10.1128/jvi.02683-06 ◽

2007 ◽

Vol 81 (16) ◽

pp. 8507-8514 ◽

Cited By ~ 40

Author(s):

Morgane Rolland ◽

Mark A. Jensen ◽

David C. Nickle ◽

Jian Yan ◽

Gerald H. Learn ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Biologically Active ◽

Recent Common Ancestor ◽

Subtype B ◽

Starting Point ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The extensive diversity of human immunodeficiency virus type 1 (HIV-1) and its capacity to mutate and escape host immune responses are major challenges for AIDS vaccine development. Ancestral sequences, which minimize the genetic distance to circulating strains, provide an opportunity to design immunogens with the potential to elicit broad recognition of HIV epitopes. We developed a phylogenetics-informed algorithm to reconstruct ancestral HIV sequences, called Center of Tree (COT). COT sequences have potentially significant benefits over isolate-based strategies, as they minimize the evolutionary distances to circulating strains. COT sequences are designed to surmount the potential pitfalls stemming from sampling bias with the consensus method and outlier bias with the most-recent-common-ancestor approach. We computationally derived COT sequences from circulating HIV-1 subtype B sequences for the genes encoding the major viral structural protein (Gag) and two regulatory proteins, Tat and Nef. COT genes were synthesized de novo and expressed in mammalian cells, and the proteins were characterized. COT Gag was shown to generate virus-like particles, while COT Tat transactivated gene expression from the HIV-1 long terminal repeat and COT Nef mediated downregulation of cell surface major histocompatibility complex class I. Thus, retrodicted ancestral COT proteins can retain the biological functions of extant HIV-1 proteins. Additionally, COT proteins were immunogenic, as they elicited antigen-specific cytotoxic T-lymphocyte responses in mice. These data support the utility of the COT approach to create novel and biologically active ancestral proteins as a starting point for studies of the structure, function, and biological fitness of highly variable genes, as well as for the rational design of globally relevant vaccine candidates.

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