Human immunodeficiency virus (HIV), comprising two distinct types, HIV-1 and HIV-2, remains one of the most significant global health challenges, originating from multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) in the early 20th century. This review traces the evolutionary trajectory of HIV from zoonotic spillover to its establishment as a global pandemic. HIV-1, the principal strain responsible for AIDS, emerged from SIVcpz in Central African chimpanzees, with phylogenetic evidence indicating initial human transmission between the 1920s and 1940s in present day Democratic Republic of Congo. The virus disseminated through colonial trade networks, reaching the Caribbean by the 1960s before establishing endemic transmission in North America and Europe. HIV’s extraordinary genetic diversity—driven by high mutation rates (~10⁻⁵ mutations per base per replication cycle) and frequent recombination events—has generated multiple groups, subtypes, and circulating recombinant forms (CRFs) with distinct epidemiological patterns. HIV-1 Group M, comprising subtypes A through L, accounts for over 95% of global infections, with subtype C predominating in sub-Saharan Africa and Asia, while subtype B dominates in Western Europe and North America. The extensive genetic heterogeneity of HIV significantly impacts diagnostic accuracy, antiretroviral therapy efficacy, and vaccine development, as subtypes exhibit differential biological properties, transmission efficiencies, and drug resistance profiles. Contemporary advances, including next-generation sequencing (NGS) for surveillance, broadly neutralizing antibodies for cross-subtype prevention and therapy, and long-acting antiretroviral formulations to improve adherence, have transformed HIV management and prevention strategies. NGS enables near real-time surveillance of drug resistance mutations and inference of transmission networks where it is available, although access and routine application remain uneven across regions. Broadly neutralizing antibodies demonstrate cross-subtype efficacy, while long-acting formulations have the potential to improve treatment adherence. This review synthesizes recent evidence and offers actionable recommendations to optimize clinical and public health responses—including the routine use of genotypic resistance testing where feasible, targeted use of phylogenetic analysis for outbreak investigation, and the development of region-specific diagnostic and treatment algorithms informed by local subtype prevalence. While the understanding of HIV’s evolutionary dynamics has substantially improved and remains essential, translating this knowledge into universally implemented intervention strategies remains a key challenge for achieving the UNAIDS 95-95-95 targets and the goal of ending AIDS as a public health threat by 2030.

HIV-1 subtype CRF01_AE is the second most predominant strain in Bulgaria, yet little is known about the molecular epidemiology of its origin and transmissibility. We used a phylodynamics approach to better understand this sub-epidemic by analyzing 270 HIV-1 polymerase (pol) sequences collected from persons diagnosed with HIV/AIDS between 1995 and 2019. Using network analyses at a 1.5% genetic distance threshold (d), we found a large 154-member outbreak cluster composed mostly of persons who inject drugs (PWID) that were predominantly men. At d = 0.5%, which was used to identify more recent transmission, the large cluster dissociated into three clusters of 18, 12, and 7 members, respectively, five dyads, and 107 singletons. Phylogenetic analysis of the Bulgarian sequences with publicly available global sequences showed that CRF01_AE likely originated from multiple Asian countries, with Vietnam as the likely source of the outbreak cluster between 1988 and 1990. Our findings indicate that CRF01_AE was introduced into Bulgaria multiple times since 1988, and infections then rapidly spread among PWID locally with bridging to other risk groups and countries. CRF01_AE continues to spread in Bulgaria as evidenced by the more recent large clusters identified at d = 0.5%, highlighting the importance of public health prevention efforts in the PWID communities.

The increased life expectancy of PLHIV (People Living with HIV) and the successful highly combined antiretroviral therapy (cART) poses new clinical challenges regarding aging and its co-morbid condition. It is commonly believed that HIV infection “accelerates” aging. Human immunodeficiency virus type 1 (HIV-1) infection is characterized by inflammation and immune activation that persists despite cART, and that may contribute to the development of co-morbid conditions. In this regard, we aimed to compare current cART regimens in light of premature aging to evaluate differences in their ability to reduce immune activation and inflammation in virologically suppressed patients. We studied a panel of biomarkers (IFN-γ, IL-1β, IL-12p70, IL-2, IL-4, IL-5, IL-6, IL-13, IL-18, GM-CSF, TNF-α, C-reactive protein, D-dimer, soluble CD14), which could provide a non-invasive and affordable approach to monitor HIV-related chronic inflammation. The results of the current study do not provide hard evidence favoring a particular cART regimen, although they show a less favorable regimen profile containing a protease inhibitor. Our data suggest an incomplete reduction of inflammation and immune activation in terms of the effective cART. It is likely that the interest in various biomarkers related to immune activation and inflammation as predictors of clinical outcomes among PLHIV will increase in the future.

In a representative nationwide study, we have determined the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfections among HIV-positive patients diagnosed during the period 2010–2014 in Bulgaria. Despite a relatively low rate of new HIV diagnoses, the rates of hepatitis B and C coinfections among these patients fell within the upper range reported in Europe. HBsAg and HCV antibodies (Ab) were found in 10.4% and 25.6% of the tested individuals, respectively. Importantly, high rates of active hepatitis infections were confirmed by detection of HBV DNA in 51.1% and HCV RNA in 78.1% of the tested individuals. Hepatitis coinfections affected mostly high risk groups and persons with multiple risk behavior, including people who inject drugs, men who have sex with men, prisoners, and Roma people.

The rate of HIV infection in Bulgaria is low. However, the rate of HCV-HIV-coinfection and HCV infection is high, especially among high-risk communities. The molecular epidemiology of those infections has not been studied before. Consensus Sanger sequences of HVR1 and NS5B from 125 cases of HIV/HCV coinfections, collected during 2010–2014 in 15 different Bulgarian cities, were used for preliminary phylogenetic evaluation. Next-generation sequencing (NGS) data of the hypervariable region 1 (HVR1) analyzed via the Global Hepatitis Outbreak and Surveillance Technology (GHOST) were used to evaluate genetic heterogeneity and possible transmission linkages. Links between pairs that were below and above the established genetic distance threshold, indicative of transmission, were further examined by generating k-step networks. Preliminary genetic analyses showed predominance of HCV genotype 1a (54%), followed by 1b (20.8%), 2a (1.4%), 3a (22.3%) and 4a (1.4%), indicating ongoing transmission of many HCV strains of different genotypes. NGS of HVR1 from 72 cases showed significant genetic heterogeneity of intra-host HCV populations, with 5 cases being infected with 2 different genotypes or subtypes and 6 cases being infected with 2 strains of same subtype. GHOST revealed 8 transmission clusters involving 30 cases (41.7%), indicating a high rate of transmission. Four transmission clusters were found in Sofia, three in Plovdiv, and one in Peshtera. The main risk factor for the clusters was injection drug use. Close genetic proximity among HCV strains from the 3 Sofia clusters, and between HCV strains from Peshtera and one of the two Plovdiv clusters confirms a long and extensive transmission history of these strains in Bulgaria. Identification of several HCV genotypes and many HCV strains suggests a frequent introduction of HCV to the studied high-risk communities. GHOST detected a broad transmission network, which sustains circulation of several HCV strains since their early introduction in the 3 cities. This is the first report on the molecular epidemiology of HIV/HCV coinfections in Bulgaria.