T-cell Decline Research Articles

Alloreactive T cells temporarily increased in the peripheral blood of patients before liver allograft rejection.

T cells are key mediators of alloresponse during liver transplantation (LTx). However, the dynamics of donor-reactive T-cell clones in peripheral blood during a clinical T-cell-mediated rejection (TCMR) episode remain unknown. Here, we collected serial peripheral blood mononuclear cell samples spanning from pre-LTx to 1 year after LTx and available biopsies during the TCMR episodes from 26 rejecting patients, and serial peripheral blood mononuclear cell samples were collected from 96 nonrejectors. Immunophenotypic and repertoire analyses were integrated on T cells from rejectors, and they were longitudinally compared to nonrejected patients. Donor-reactive T-cell clone was identified and tracked by cross-matching with the mappable donor-reactive T-cell receptor repertoire of each donor-recipient pair in 9 rejectors and 5 nonrejectors. Before transplantation, the naive T-cell percentage and T-cell receptor repertoire diversity of rejectors was comparable to that of healthy control, but it was reduced in nonrejectors. After transplantation, the naïve T-cell percentages decreased, and T-cell receptor repertoires were skewed in rejectors; the phenomenon was not observed in nonrejectors. Alloreactive clones increased in proportion in the peripheral blood of rejectors before TCMR for weeks. The increase was accompanied by the naïve T-cell decline and memory T-cell increase and acquired an activated phenotype. Intragraft alloreactive clone tracking in pre-LTx and post-LTx peripheral blood mononuclear cell samples revealed that the pretransplant naïve T cells were significant contributors to the donor-reactive clones, and they temporarily increased in proportion and subsequently reduced in blood at the beginning of TCMR. Together, our findings offer an insight into the dynamic and origin of alloreactive T cells in clinical LTx TCMR cases and may facilitate disease prediction and management.

Naïve T-cell decline is a significant contributor to expression changes in ageing blood.

No clear consensus has emerged from the literature on the gene expression changes that occur in human whole blood with age. In this study we compared whole blood ageing genes from the published literature with data on gene specificity for leukocyte subtypes. Surprisingly we found that highly ranked ageing genes were predominantly expressed by naïve T cells, with limited expression from more common cell types. Highly ranked ageing genes were also more likely to have decreased expression with age. Taken together, it is plausible that much of the observed gene expression changes in whole blood is reflecting the decline in abundance of naïve T cells known to occur with age, rather than changes in transcription rates in common cell types. Correct attribution of the gene expression changes that occur with age is essential for understanding the underlying mechanisms.

A metagenome-wide association study of HIV disease progression in HIV controllers

Some HIV controllers experience immunologic progression with CD4+ Tcell decline. We aimed to identify genetic factors associated with CD4+ Tcell lost in HIV controllers. A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p= 0.005; OR= 1.70], rs59440261 [p= 0.003; OR= 1.78]), MICA (rs112243036 [p= 0.011; OR= 1.45]), and PSORS1C1 loci (rs3815087 [p= 0.017; OR= 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype.

A population-level application of a method for estimating the timing of HIV acquisition among migrants to Australia.

Australia has set the goal for the virtual elimination of HIV transmission by the end of 2022, yet accurate information is lacking on the level of HIV transmission occurring among residents. We developed a method for estimating the timing of HIV acquisition among migrants, relative to their arrival in Australia. We then applied this method to surveillance data from the Australian National HIV Registry with the aim of ascertaining the level of HIV transmission among migrants to Australia occurring before and after migration, and to inform appropriate local public health interventions. We developed an algorithm incorporating CD4+ T-cell decline back-projection and enhanced variables (clinical presentation, past HIV testing history and clinician estimate of the place of HIV acquisition) and compared it to a standard algorithm which uses CD4+ T-cell back-projection only. We applied both algorithms to all new HIV diagnoses among migrants to estimate whether HIV infection occurred before or after arrival in Australia. Between 1 January 2016 and 31 December 2020, 1909 migrants were newly diagnosed with HIV in Australia, 85% were men, and the median age was 33 years. Using the enhanced algorithm, 932 (49%) were estimated to have acquired HIV after arrival in Australia, 629 (33%) before arrival (from overseas), 250 (13%) close to arrival and 98 (5%) were unable to be classified. Using the standard algorithm, 622 (33%) were estimated to have acquired HIV in Australia, 472 (25%) before arrival, 321 (17%) close to arrival and 494 (26%) were unable to be classified. Using our algorithm, close to half of migrants diagnosed with HIV were estimated to have acquired HIV after arrival in Australia, highlighting the need for tailored culturally appropriate testing and prevention programmes to limit HIV transmission and achieve elimination targets. Our method reduced the proportion of HIV cases unable to be classified and can be adopted in other countries with similar HIV surveillance protocols, to inform epidemiology and elimination efforts.

The State of the HIV Epidemic in the Philippines: Progress and Challenges in 2023.

In the past decade, the Philippines has gained notoriety as the country with the fastest-growing human immunodeficiency virus (HIV) epidemic in the Western Pacific region. While the overall trends of HIV incidence and acquired immunodeficiency syndrome (AIDS)-related deaths are declining globally, an increase in new cases was reported to the HIV/AIDS and ART Registry of the Philippines. From 2012 to 2023, there was a 411% increase in daily incidence. Late presentation in care remains a concern, with 29% of new confirmed HIV cases in January 2023 having clinical manifestations of advanced HIV disease at the time of diagnosis. Men having sex with men (MSM) are disproportionately affected. Various steps have been taken to address the HIV epidemic in the country. The Philippine HIV and AIDS Policy Act of 2018 (Republic Act 11166) expanded access to HIV testing and treatment. HIV testing now allows for the screening of minors 15-17 years old without parental consent. Community-based organizations have been instrumental in expanding HIV screening to include self-testing and community-based screening. The Philippines moved from centralized HIV diagnosis confirmation by Western blot to a decentralized rapid HIV diagnostic algorithm (rHIVda). Dolutegravir-based antiretroviral therapy is now the first line. Pre-exposure prophylaxis in the form of emtricitabine-tenofovir disoproxil fumarate has been rolled out. The number of treatment hubs and primary HIV care facilities continues to increase. Despite these efforts, barriers to ending the HIV epidemic remain, including continued stigma, limited harm reduction services for people who inject drugs, sociocultural factors, and political deterrents. HIV RNA quantification and drug resistance testing are not routinely performed due to associated costs. The high burden of tuberculosis and hepatitis B virus co-infection complicate HIV management. CRF_01AE is now the predominant subtype, which has been associated with poorer clinical outcomes and faster CD4 T-cell decline. The HIV epidemic in the Philippines requires a multisectoral approach and calls for sustained political commitment, community involvement, and continued collaboration among various stakeholders. In this article, we outline the current progress and challenges in curbing the HIV epidemic in the Philippines.

Estradiol-independent restoration of T-cell function in post-reproductive females.

Aging leads to a general decline in protective immunity. The most common age-associated effects are in seen T-cell mediated immune function. Adult mice whose immune systems show only moderate changes in T-cell subsets tend to live longer than age-matched siblings that display extensive T-cell subset aging. Importantly, at the time of reproductive decline, the increase in disease risks in women significantly outpace those of men. In female mice, there is a significant decline in central and peripheral naïve T-cell subsets at the time of reproductive failure. Available evidence indicates that this naïve T-cell decline is sensitive to ovarian function and can be reversed in post-reproductive females by transplantation of young ovaries. The restoration of naïve T-cell subsets due to ovarian transplantation was impressive compared with post-reproductive control mice, but represented only a partial recovery of what was lost from 6 months of age. Apparently, the influence of ovarian function on immune function may be an indirect effect, likely moderated by other physiological functions. Estradiol is significantly reduced in post-reproductive females, but was not increased in post-reproductive females that received new ovaries, suggesting an estradiol-independent, but ovarian-dependent influence on immune function. Further evidence for an estradiol-independent influence includes the restoration of immune function through the transplantation of young ovaries depleted of follicles and through the injection of isolated ovarian somatic cells into the senescent ovaries of old mice. While the restoration of naïve T-cell populations represents only a small part of the immune system, the ability to reverse this important functional parameter independent of estradiol may hold promise for the improvement of post-reproductive female immune health. Further studies of the non-reproductive influence of the ovary will be needed to elucidate the mechanisms of the relationship between the ovary and health.

Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART.

Human immunodeficiency virus (HIV) can persist as an integrated provirus, in a transcriptionally repressed state, within infected cells. This small yet enduring pool of cellular reservoirs that harbor replication-competent HIV is the main barrier to cure. Entry of viral sequences into cellular reservoirs begins shortly after infection, and cells containing integrated proviral DNA are extremely stable once suppressive antiretroviral therapy (ART) is initiated. During untreated HIV infection however, reservoir turnover is likely to be more dynamic. Understanding these dynamics is important because the longevity of the persisting proviral pool during untreated infection dictates reservoir composition at ART initiation. If the persisting proviral pool turns over slowly pre-ART, then HIV sequences seeded into it during early infection would have a high likelihood of persisting for long periods. However, if pre-ART turnover was rapid, the persisting proviral pool would rapidly shift toward recently circulating HIV sequences. One-way to estimate this turnover rate is from the age distributions of proviruses sampled shortly after therapy initiation: this is because, at the time of sampling, the majority of proviral turnover would have already occurred prior to ART. Recently, methods to estimate a provirus’ age from its sequence have made this possible. Using data from 12 individuals with HIV subtype C for whom proviral ages had been determined phylogenetically, we estimated that the average proviral half-life during untreated infection was 0.78 (range 0.45–2.38) years, which is >15 times faster than that of proviral DNA during suppressive ART. We further show that proviral turnover during untreated infection correlates with both viral setpoint and rate of CD4+ T-cell decline during this period. Overall, our results support dynamic proviral turnover pre-ART in most individuals, which helps explain why many individuals’ reservoirs are skewed toward younger HIV sequences. Broadly, our findings are consistent with the notion that active viral replication creates an environment less favorable to proviral persistence, while viral suppression creates conditions more favorable to persistence, where ART stabilizes the proviral pool by dramatically slowing its rate of decay. Strategies to inhibit this stabilizing effect and/or to enhance reservoir turnover during ART could represent additional strategies to reduce the HIV reservoir.

Comparison of predictors for terminal disease progression in simian immunodeficiency virus/simian-HIV-infected rhesus macaques.

CD4+ T-cell decline and increasing virus levels are considered hallmarks of HIV/AIDS pathogenesis but we previously demonstrated in rhesus macaques that tissue macrophage destruction by simian immunodeficiency virus (SIV) infection associated with increased monocyte turnover also appear to impact pathogenesis. It remains unclear, however, which factors best predict onset of terminal disease progression and survival time. The objective of this study, therefore, was to directly compare these co-variates of infection for predicting survival times in retrospective studies of SIV/simian-HIV (SHIV)-infected adult rhesus macaques. Rhesus macaques were infected with various strains of SIV/SHIV and evaluated longitudinally for monocyte turnover, CD4+ T-cell loss, plasma viral load, and SIV/SHIV strain. Correlation analyses and machine learning algorithm modeling were applied to compare relative contributions of each of the co-variates to survival time. All animals with AIDS-related clinical signs requiring euthanasia exhibited increased monocyte turnover regardless of CD4+ T-cell level, viral strain, or plasma viral load. Regression analyses and machine learning algorithms indicated a stronger correlation and contribution between increased monocyte turnover and reduced survival time than between CD4+ T-cell decline, plasma viral load, or virus strain and reduced survival time. Decision tree modeling categorized monocyte turnover of 13.2% as the initial significant threshold that best predicted decreased survival time. These results demonstrate that monocytes/macrophages significantly affect HIV/SIV pathogenesis outcomes. Monocyte turnover analyses are not currently feasible in humans, so there is a need to identify surrogate biomarkers reflecting tissue macrophage damage that predict HIV infection disease progression.

Mimicking SIV chimpanzee viral evolution toward HIV-1 during cross-species transmission.

HIV-1 evolved from SIV during cross-species transmission events, though viral genetic changes are not well understood. Here, we studied the evolution of SIVcpzLB715 into HIV-1 Group M using humanized mice. High viral loads, rapid CD4+ T-cell decline, and non-synonymous substitutions were identified throughout the viral genome suggesting viral adaptation.

Evolution of SIVsm in humanized mice towards HIV-2.

Through the accumulation of adaptive mutations, HIV-2 originated from SIVsm. To identify these evolutionary changes, a humanized mouse model recapitulated the process that likely enabled this cross-species transmission event. Various adaptive mutations arose, as well as increased virulence and CD4+ T-cell decline as the virus was passaged in humanized mice.

The impact of bone marrow stromal antigen-2 (BST2) gene variants on HIV-1 control in black South African individuals

Bone marrow stromal cell antigen 2 (BST2 or tetherin) is a host-encoded, interferon-inducible antiviral restriction factor which blocks the release of enveloped viruses. Few studies have assessed the role of BST2 polymorphisms on HIV-1 acquisition or disease progression in sub-Saharan Africa. This study investigated the frequency of four HIV-1-associated BST2 variants rs3217318, rs12609479, rs10415893 and rs113189798 in uninfected and HIV-1 infected black South Africans. Homozygosity for the rs12609479-A minor allele, previously associated with decreased HIV-1 acquisition risk, was underrepresented in HIV-1 uninfected black South Africans (2%) compared to reference African (9%) and in particular European populations (61%) (p = .047 and p < .0001, respectively). To determine if any of these gene variants influenced HIV-1 control in the absence of antiretroviral treatment (ART), we compared HIV-1 infected ART-naïve progressors [n = 72] and controllers [n = 71], the latter includes elite controllers [EC: n = 23; VL < 50 RNA copies/ml]. Heterozygosity for the rs12609479 SNP (G/A) was enriched in progressors compared to ECs (47.2% vs 21.7%, OR = 3.50 [1.16–10.59], p = .03), while rs113189798 heterozygosity (A/G) showed a strong trend of overrepresentation in ECs compared to progressors (47.8% vs 26.4%, OR = 0.39 [0.14–1.04], p = .07). Heterozygosity for the promoter indel rs3217318 (i19/Δ19) was associated with a faster rate of CD4+ T-cell decline in progressors (p = .0134). Carriage of the rs3217318 (i19/Δ19), rs12609479 (G/G), rs10415893(G/A) and rs113189798 (A/G) combined genotype, denoted as i19Δ19 GG GA AG, was associated with significantly higher CD4+ T-cell counts in progressors (p = .03), a finding predominantly driven by the _GG_AG combination. Our data suggest that the possession of select BST2 genotype combinations may be implicated in HIV-1 disease progression and natural spontaneous control.

Triple HIV-1 Infection Is Associated With Faster CD4+ T-Cell Decline.

HIV-1 dual infection occurs when an individual is simultaneously or sequentially infected with two or more genetically distinct HIV-1 strains. According to the number of infected strains, HIV-1 dual infection can be divided in double infection and triple infection and so on. Currently, the majority of dual infection cases have been reported to be double infections which can result in detrimental clinical outcomes. The high incidence of double infection among specific high-risk populations increases the likelihood of triple infection, which has been sporadically described. There is no doubt that we are concerned about the association between triple infection and disease progression. However, this relationship is still unclear on the population level. In this study, 70 individuals from the Beijing PRIMO cohort were longitudinally followed up with a median time of 15.75 months for the purpose of investigating the incidence of dual infection. Phylogenetic analyses using bulk and single-genome sequences showed that nine individuals acquired double infection, with the incidence of 9.21 per 100 person-years, and three individuals with triple infection were identified, with the incidence of 3.07 per 100 person-years. The further survival analysis demonstrated that the triple infection group exhibited faster CD4+ T-cell decline. In summary, these results demonstrate for the first time that the triple HIV-1 infection might reduce CD4+ T-cell counts, which would predict a more rapid disease progression.

Towards Understanding & Uncovering New Key Players in T-Cell Development upon Aging

Aging-associated immune remodeling (AAIR) leads to an impaired ability to respond to vaccination and combat infections, and is due to many factors acting in concert. Several studies have linked the T-cell decline that occurs with age to thymic involution. However, there is novel and mounting evidence that also aged lymphoid-primed multipotent progenitors (LMPPs) are immune system intrinsic players in AAIR. However, very little is known on molecular and cellular mechanisms by which aging LMPPs could drive this AAIR phenomenon. Deciphering the underlying mechanisms is of crucial importance for developing new therapies to attenuate AAIR. Here, we present new data demonstrating the dysregulated pathways associated with aged LMPPs and the cellular changes in early thymic differentiation events in driving AAIR. To assess the T-lineage potential of aged LMPPs, we performed single cells ex-vivo OP9D assays using LMPPs (Lin-cKit+Sca1+CD34-Flt3hi) from aged (18-20 month-old) and young (8-10 week-old) C57BL/6 animals as controls. The frequencies of T-cell lineage potential in aged LMPPs and young LMPPs at the single cell level were very similar. This result was also validated in vivo by transplantation assays where 5000 aged or young LMPPs were injected into sub-lethally irradiated young recipients followed by T-cell lineage (CD4+ &amp; CD8+) analysis in the peripheral blood (PB) at 4 weeks post transplantation (Mean; Y:12,75 vs A:16:23 % of total, p=0.46). However, aged LMPPs were associated with a dramatic disadvantage of PB T-cells at 4 weeks post injections (Mean; Y:9 vs A:2.3 % of total, p&lt;0.0001) and in the development of all thymic stages of thymocytes, from early double negative stage CD4-CD8-(DN1) (Mean; Y:30 vs A:8 % of parent, p&lt;0.0001) to double positive stage CD4+CD8+(DP) (Mean; Y:53 vs A:15 % of parent, p&lt;0.0001), as well as single positive (SP) CD4+(Mean; Y:54 vs A:13 % of parent, p&lt;0.0001) and CD8+(Mean; Y:45 vs A:10 % of parent, p&lt;0.0001) thymocytes when intravenously transplanted in combination with 1:1 ratio of young LMPPs into young recipients. To overcome a potential homing to the thymus bias of aged LMPPs in competitive transplants, we performed intra-thymic injections of young and aged LMPPs with identical ratios into sub-lethally irradiated young recipients. The analysis of PB at 4 weeks post injections show a dramatic reduction of PB T-cells derived from aged LMPPs in comparison with young LMPPs (Mean; Y:14.8 vs A:8 % of total, p&lt;0.0001). There was primarily a strong disadvantage towards generating DP stage (Mean; Y:46 vs A:28 % of parent, p&lt;0.0001), suggesting that the intra-thymic injections indeed alleviated the dramatic decrease in the early thymocyte stage DN1 (Mean; Y:31 vs A:22 % of parent, p&lt;0.05). This suggests that aged LMPPs confer a T-cell differentiation and maybe an additional homing to the thymus defect. We also performed RNA-Seq analyses on LMPPs from young and aged mice. Unsupervised hierarchical clustering of differentially expressed genes between young and aged LMPPs highlighted a clear dysregulation of only a few pathways that are involved in T-cell development such as Notch signaling. We next correlated our RNA-Seq data with other immunological signatures in attempt to look for more T-cell specific key factors that are differentially expressed between young and aged LMPPs. Importantly, the results show that the data from our RNA-Seq correlated with more than 400 immunological signatures among which 25 were most highly correlated. Interestingly, this correlation has allowed us to curate a list of the top 30 differentially expressed genes between young and aged LMPPs including T-cell specific transcription factors such as Satb1 and Foxo1. Altogether, our findings reveal that the T-cell immune decline that occurs with age is already imprinted in LMPPs within the bone marrow and translates into a dysregulation of signaling pathways that are directly related to T-cell development. Targeting these pathways could open up new perspectives in attenuating AAIR. Disclosures No relevant conflicts of interest to declare.

SIVcpz cross-species transmission and viral evolution toward HIV-1 in a humanized mouse model.

HIV-1 evolved from its progenitor SIV strains, but details are lacking on its adaptation to the human host. We followed the evolution of SIVcpz in humanized mice to mimic cross-species transmission. Increasing viral loads, CD4+ T-cell decline, and non-synonymous mutations were seen in the entire genome reflecting viral adaptation.

Role of T-cell trafficking in the pathogenesis of HIV disease.

Trafficking of lymphocytes into and between gut inductive and effector sites of the gut tissues is regulated by integrin α4β7. Recent findings that describe the central role of α4β7 CD4 T cells in HIV pathogenesis, and the possibility of targeting these cells to prevent or treat HIV infection will be reviewed. Recent reports indicate that the frequency of α4β7 CD4 T cells is directly correlated with the risk of HIV acquisition and CD4 T-cell decline post infection. MAdCAM -mediated signaling through α4β7, in the presence of retinoic acid, supports viral replication in recently activated naïve CD4 T cells. Treatment of HIV-infected patients with vedolizumab, an α4β7 antagonist, is well tolerated, and reduces the size and number of lymphoid aggregates in gut associated lymphoid tissues. Integrin α4β7 underlies one of the principal mechanisms that CD4 T cells employ to traffic to the gut. It also defines a subset of cells that play a significant role in HIV transmission and pathogenesis. Understanding how α4β7 facilitates gut homing may provide insight into key aspects of HIV transmission, pathogenesis, and the formation of viral reservoirs. Targeting α4β7 may have utility in the prevention and treatment of HIV infection.

Rapid CD4+ T-cell decline is associated with coreceptor switch among MSM primarily infected with HIV-1 CRF01_AE in Northeast China.

CRF01_AE is the most prevalent HIV-1 subtype among MSM in China. However, the characteristics and underlying mechanism of the accelerated CD4 T-cell decline in CRF01_AE-infected MSM remain incompletely understood. A long-term prospective follow-up study was conducted with 1388 MSM at risk of HIV-1 infection in Northeast China. MSM with primary HIV-1 CRF01_AE infection were identified and followed for 3-6 years to explore the determinants of rapid CD4 T-cell decline. Tropism was determined in primary infection by both single genome amplification-based genotypic prediction using four different algorithms and phenotypic determination using clinical isolates. Serial isolates were used to determine phenotype of coreceptor switch. Human leukocyte antigen genotypes and T-cell activation markers were determined. Fifty-nine MSM primarily infected with HIV-1 CRF01_AE were discovered and recruited for the follow-up study. CCR5-utilizing (R5) viruses accounted for up to 98% of HIV-1 CRF01_AE infections in Northeast China. Survival analysis indicated 39.5% of the patients underwent coreceptor switch within 3 years after infection. After adjustment for other potential risk factors, linear mixed-effect models demonstrated patients experienced R5 to CXCR4-utilizing/dual-tropic (X4/DM) coreceptor switch within 3 years after infection underwent a faster CD4 T-cell decline compared to those without coreceptor switch. Primary HIV-1 CRF01_AE infection among MSM in Northeast China is characterized by R5 viral infection and early R5 to X4/DM coreceptor switch, which is associated with rapid CD4 T-cell decline. The findings highlight the importance of immediate treatment among the CRF01_AE-infected MSM.

Fc-gamma receptor IIA and IIIA variants in two African cohorts: Lack of consistent impact on heterosexual HIV acquisition, viral control, and disease progression

Human Fc-gamma receptors (FcγRs) FcγRIIA and FcγRIIIA contain amino acid variants with both high and low affinities for IgG that modulate antibody-mediated effector functions. Recent HIV vaccine trials suggested that these FcγR variants can influence susceptibility to HIV infection, which prompted us to fully assess the role of FcγR variants on HIV acquisition, viral control, and disease progression in two longitudinal heterosexual transmission cohorts with HIV subtypes A and C as the major circulating viruses. For 836 participants, molecular genotyping resolved genetic variations encoding the FcγRIIA (131 H/R) and FcγRIIIA (158 V/F) single nucleotide polymorphisms. Kaplan-Meier curves, Cox proportional hazards models, and linear regression models did not reveal any clear or consistent FcγR association with time to HIV acquisition, viral load in early infection, or extent of CD4 + T-cell decline over time after infection. Overall, previous epidemiological findings on FcγR variants and vaccine efficacy are not readily applicable to heterosexual HIV transmission.

Increase in transmitted drug resistance in migrants from sub-Saharan Africa diagnosed with HIV-1 in Sweden.

To study the trends of transmitted drug resistance (TDR) in HIV-1 patients newly diagnosed in Sweden, 2010-2016. Register-based study including all antiretroviral therapy-naive patients ≥18 years diagnosed with HIV-1 in Sweden 2010-2016. Patient data and viral pol sequences were extracted from the national InfCareHIV database. TDR was defined as the presence of surveillance drug resistance mutations (SDRMs). A CD4 T-cell decline trajectory model estimated time of infection. Phylogenetic inference was used for cluster analysis. Chi-square tests and logistic regressions were used to investigate relations between TDR, epidemiological and viral factors. One thousand, seven hundred and thirteen pol sequences were analyzed, corresponding to 71% of patients with a new HIV-1 diagnosis (heterosexuals: 53%; MSM: 34%). The overall prevalence of TDR was 7.1% (95% CI 5.8-8.3%). Nonnucleoside reverse transcriptase inhibitor (NNRTI) TDR increased significantly from 1.5% in 2010 to 6.2% in 2016, and was associated to infection and/or origin in sub-Saharan Africa (SSA). An MSM transmission cluster dating back to the 1990s with the M41L SDRM was identified. Twenty-five (1.5%) patients exhibited TDR to tenofovir (TDF; n = 8), emtricitabine/lamivudine (n = 9) or both (n = 8). NNRTI TDR has increased from 2010 to 2016 in HIV-1-infected migrants from SSA diagnosed in Sweden, mirroring the situation in SSA. TDR to tenofovir/emtricitabine, used in preexposure prophylaxis, confirms the clinical and epidemiological need for resistance testing in newly diagnosed patients.

Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T-Cell Decline, and Per-Parasite Pathogenicity.

Pathogen strains may differ in virulence because they attain different loads in their hosts, or because they induce different disease-causing mechanisms independent of their load. In evolutionary ecology, the latter is referred to as “per-parasite pathogenicity”. Using viral load and CD4+ T-cell measures from 2014 HIV-1 subtype B-infected individuals enrolled in the Swiss HIV Cohort Study, we investigated if virulence—measured as the rate of decline of CD4+ T cells—and per-parasite pathogenicity are heritable from donor to recipient. We estimated heritability by donor–recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences. Regressing the CD4+ T-cell declines and per-parasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, our best estimate for the heritability of the CD4+ T-cell decline is 17% (5–30%), and that of the per-parasite pathogenicity is 17% (4–29%). Further, we confirm that the set-point viral load is heritable, and estimate a heritability of 29% (12–46%). Interestingly, the pattern of evolution of all these traits differs significantly from neutrality, and is most consistent with stabilizing selection for the set-point viral load, and with directional selection for the CD4+ T-cell decline and the per-parasite pathogenicity. Our analysis shows that the viral genotype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor.

Recent increased identification and transmission of HIV-1 unique recombinant forms in Sweden

A temporal increase in non-B subtypes has earlier been described in Sweden by us and we hypothesized that this increased viral heterogeneity may become a hotspot for the development of more complex and unique recombinant forms (URFs) if the epidemics converge. In the present study, we performed subtyping using four automated tools and phylogenetic analysis by RAxML of pol gene sequences (n = 5246) and HIV-1 near full-length genome (HIV-NFLG) sequences (n = 104). A CD4+ T-cell decline trajectory algorithm was used to estimate time of HIV infection. Transmission clusters were identified using the family-joining method. The analysis of HIV-NFLG and pol gene described 10.6% (11/104) and 2.6% (137/5246) of the strains as URFs, respectively. An increasing trend of URFs was observed in recent years by both approaches (p = 0·0082; p < 0·0001). Transmission cluster analysis using the pol gene of all URFs identified 14 clusters with two to eight sequences. Larger transmission clusters of URFs (BF1 and 01B) were observed among MSM who mostly were sero-diagnosed in recent time. Understanding the increased appearance and transmission of URFs in recent years could have importance for public health interventions and the use of HIV-NFLG would provide better statistical support for such assessments.