The Interferon Resistance of Transmitted HIV-1 is a Consequence of Enhanced Replicative Fitness

HIV-1 transmission via sexual exposure is a relatively inefficient process. When successful transmission does occur, newly infected individuals are colonized by either a single or a very small number of establishing virion(s). These transmitted founder (TF) viruses are more interferon (IFN) resistant than chronic control (CC) viruses present 6 months after transmission. To identify the specific molecular defences that make CC viruses more susceptible to the IFN-induced ′antiviral state′ than TF viruses, we established a pair of fluorescent GFP-IRES-Nef TF and CC viruses and used arrayed interferon-stimulated gene (ISG) expression screening. The relatively uniform ISG resistance of transmitted HIV-1 directed us to investigate the underlying mechanism. Our subsequent in silico simulations, modelling, and in vitro characterisation of a model TF/CC pair (closely matched in replicative fitness), revealed that small differences in replicative growth rates can explain the broad IFN resistance displayed by transmitted HIV-1. We propose that the apparent IFN resistance of transmitted HIV-1 is a consequence of enhanced replicative fitness, as opposed to specific resistance to individual IFN-induced defences.

The P681H mutation in the Spike glycoprotein confers Type I interferon resistance in the SARS-CoV-2 alpha (B.1.1.7) variant

Variants of concern (VOCs) of severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) threaten the global response to the COVID-19 pandemic. The alpha (B.1.1.7) variant appeared in the UK became dominant in Europe and North America in early 2021. The Spike glycoprotein of alpha has acquired a number mutations including the P681H mutation in the polybasic cleavage site that has been suggested to enhance Spike cleavage. Here, we show that the alpha Spike protein confers a level of resistance to the effects of interferon-β (IFNβ) in lung epithelial cells. This correlates with resistance to restriction mediated by interferon-induced transmembrane protein-2 (IFITM2) and a pronounced infection enhancement by IFITM3. Furthermore, the P681H mutation is necessary for comparative resistance to IFNβ in a molecularly cloned SARS-CoV-2 encoding alpha Spike. Overall, we suggest that in addition to adaptive immune escape, mutations associated with VOCs also confer replication advantage through adaptation to resist innate immunity.

Interferon Resistance of Emerging SARS-CoV-2 Variants

The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity may drive the emergence of these novel variants, studies documenting a critical a role for interferon responses in the early control of SARS-CoV-2 infection, combined with the presence of viral genes that limit these responses, suggest that interferons may also influence SARS-CoV-2 evolution. Here, we compared the potency of 17 different human interferons against 5 viral lineages sampled during the course of the global outbreak that included ancestral and emerging variants. Our data revealed increased interferon resistance in emerging SARS-CoV-2 variants, indicating that evasion of innate immunity is a significant driving force for SARS-CoV-2 evolution. These findings have implications for the increased lethality of emerging variants and highlight the interferon subtypes that may be most successful in the treatment of early infections.

TREATMENT OF HCV INFECTION BY A COMBINATION OF SOFOSBUVIR AND DACLATASVIR

The purpose of the review is to evaluate the efficacy and safety of using pangenotypic combination «of Sofosbuvir/Daclatasvir» — the direct action antiviral drugs in the treatment of chronic HCV infection at different stages of liver damage.Main provisions: Sofosbuvir is the antisense nucleotide, inhibiting RNA-dependent RNA-polymerase NS5B, this drug has earned a reputation as one of the strongest anti-replication drugs, including when there is interferon resistance. Daclatasvir is a powerful non-nucleotide inhibitor of NS5А protein, catalyzing formation of replicative complexes. Both components are proven to be effect against HCV genotypes 1-6. Their combination provides pangenotypic activity, and the mutual strengthening effect diminishes the risk of development of drug resistance. Indications for the administration of a combination «Sofosbuvir/Daclatasvi» are: treatment of HCV infection at the stage of acute hepatitis (for genotypes 1–6 of the virus), treatment for HCV infection at the stage of chronic hepatitis (for genotypes 1–6 of the virus), treatment of HCV infection in co-infection with HIV, treatment of HCV infection at the stage of liver cirrhosis, treatment of recurrent HCV infection after liver transplantation, treatment of HCV infection with immune manifestations.Conclusion: the combination «Sofosbuvir/Daclatasvir» is shown to be highly effective in the treatment of HCV infection of genotypes 1-6 with a frequency of SVR 93—97% at the stage of the hepatitis and 88—95% — at the stage of cirrhosis. Good tolerance and high efficiency has led to active use of this combination фе the stage of cirrhosis. This combination has been successfully used for the treatment of recurrence of HCV infection in the liver graft, including co-infection with HIV.

Vpu-Mediated Counteraction of Tetherin Is a Major Determinant of HIV-1 Interferon Resistance

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) groups M, N, O, and P are the result of independent zoonotic transmissions of simian immunodeficiency viruses (SIVs) infecting great apes in Africa. Among these, only Vpu proteins of pandemic HIV-1 group M strains evolved potent activity against the restriction factor tetherin, which inhibits virus release from infected cells. Thus, effective Vpu-mediated tetherin antagonism may have been a prerequisite for the global spread of HIV-1. To determine whether this particular function enhances primary HIV-1 replication and interferon resistance, we introduced mutations into thevpugenes of HIV-1 group M and N strains to specifically disrupt their ability to antagonize tetherin, but not other Vpu functions, such as degradation of CD4, down-modulation of CD1d and NTB-A, and suppression of NF-κB activity. Lack of particular human-specific adaptations reduced the ability of HIV-1 group M Vpu proteins to enhance virus production and release from primary CD4+T cells at high levels of type I interferon (IFN) from about 5-fold to 2-fold. Interestingly, transmitted founder HIV-1 strains exhibited higher virion release capacity than chronic control HIV-1 strains irrespective of Vpu function, and group M viruses produced higher levels of cell-free virions than an N group HIV-1 strain. Thus, efficient virus release from infected cells seems to play an important role in the spread of HIV-1 in the human population and requires a fully functional Vpu protein that counteracts human tetherin.IMPORTANCEUnderstanding which human-specific adaptations allowed HIV-1 to cause the AIDS pandemic is of great importance. One feature that distinguishes pandemic HIV-1 group M strains from nonpandemic or rare group O, N, and P viruses is the acquisition of mutations in the accessory Vpu protein that confer potent activity against human tetherin. Adaptation was required because human tetherin has a deletion that renders it resistant to the Nef protein used by the SIV precursor of HIV-1 to antagonize this antiviral factor. It has been suggested that these adaptations in Vpu were critical for the effective spread of HIV-1 M strains, but direct evidence has been lacking. Here, we show that these changes in Vpu significantly enhance virus replication and release in human CD4+T cells, particularly in the presence of IFN, thus supporting an important role in the spread of pandemic HIV-1.