Molecular genetics of HIV-1 Molecular genetics of HIV-1 strains spreading in Russia strains spreading in Russia

Edward Karamov

Ivanovsky Institute of Virology, Moscow

4th World Congress on Virology,6-8 October 2014, San Antonio

Worldwide: 35 mln HIV+, 35 mln diedIn 2014: 2 mln new infections

1.3 mln deaths 14 mln receive HAART

Emergence of zoonosesEmergence of zoonoses::

Adapted fromHo & Bieniasz

Cell, 2008

ABOBEC3G & TRIM5 are important for the host tropismus of HIV & SIV

Restriction factors usually have broad antiviral activity

HIV & SIV are resistant against theantiviral factors of their own hosts

Adaptation of SIVcpz to chimpanzees paved the way for the spread of HIV-1 in humans: SIVcpz is resistant against human ABOBEC3G & TRIM5

Specific features of HIV epidemic at this stage

1. The principal route of HIV transmission is still associated with intravenous drug use (60% in 2013)

2. Persons aged 15-30 account for more than 60% of the HIV-infected population

3. A steady growth in the occurrence of HIV infection among women tends to persist

4. Intravenous drug use becomes more widespread, sex industry undergoes further development

5. The number of late-stage patients in need of antiretroviral chemotherapy increases

C

16%

6%D

G

23%

F (E,H)5%

A/B0%

А

8%

В42%

А86%

В5%

C,D,G,F,H4% A/B

5%

HIV-1 subtypes in RUSSIAHIV-1 subtypes in RUSSIA

in 1994 in 2000Source: E.Karamov et al., 2000Source: E.Karamov et al., 2000

Genetic subtypes of HIVGenetic subtypes of HIV-1 -1 in Russiain Russia

A/B (4%)

A (93%)

B (2%)Homogeneity

(А - > 93%)(IDUs + heterosexuals)

Low degree ofgenetic variability

(2-8%)

Whole genome sequence of the CRF-02 A/G recombinant isolated from a patient with acute HIV-1 infection

UZBEKISTAN

Phylogenetic tree of CFRPhylogenetic tree of CFR02_02_AG recombinantsAG recombinants

94 full-genome sequences: 12 countries + the first full-genome sequence from Russia

OUTGROUPNew A1 Sequence,Moscow

New AG Sequence,Moscow

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Full-length genome sequences obtained for Full-length genome sequences obtained for ten Russian HIV isolatesten Russian HIV isolates

Mosaic structure of the CRF63_02AG recombinantMosaic structure of the CRF63_02AG recombinant

N. Shcherbakova et. al., N. Shcherbakova et. al., AIDS Research and Human RetrovirusesAIDS Research and Human Retroviruses, 2014, 2014

Biological properties of HIV Biological properties of HIV isolatesisolates

Viral strain Cell TCID50

HIV-1SK-8 PBMC 1.4∙103

HIV-1IIIB СEM-SS 3.0∙105

HIV-1Bru CEM-SS 1.6∙105

HIV-1Uganda 455 MT4 2.5∙104

HIV-1RiB-A\08 MT4 2.0∙104

Table 1. Comparison of infectious activity of HIV-1Table 1. Comparison of infectious activity of HIV-1

PBMC CEM-SS MT4 U937HIV-1SK-8 + - + -HIV-1IIIB + + + +HIV-1Bru + + + +

HIV-1Uganda 455 - + + +HIV-1RiB-A/07 + + + +

Table 2. Replication ability of HIV-1 in PBMC and diverse cell linesTable 2. Replication ability of HIV-1 in PBMC and diverse cell lines

Cells HIV-1RiB-A/07 HIV-1SK-8 Control (no

virus)U373 CD4CXCR4 3.225 2.909 0.024

U373 CD4CCR5 3.203 2.497 0.010

Table 3. Tropism of Russian HIV-1 isolates to coreceptorsTable 3. Tropism of Russian HIV-1 isolates to coreceptors

HIV-1 strain Syncytium-inducing activity Phenotype HIV-1SK-8 +/- NSI

HIV-1RiB-A/07 +/- NSIHIV-1Uganda455 +++ SI

HIV-1Bru +++ SIHIV-1IIIB ++++ SI

Table 4. Syncytium formation induced by HIV-1 strainsTable 4. Syncytium formation induced by HIV-1 strains

HIV-1 strain

AZT concentration, µМ100 10 1 0.1 0.01 0.001

HIV-1SK-8 3 4 4 6 28 75HIV-1RiB-A/07 55 65 66 78 86 82

HIV-1IIIB 9 21 23 40 58 100HIV-1Bru 0 0 2.6 27.1 88.5 88.5

Table 5. Levels of HIV-1 infection in the presence of diverse concentrations of AZT (percentages of inhibitor-free control)Table 5. Levels of HIV-1 infection in the presence of diverse concentrations of AZT (percentages of inhibitor-free control)

Isolation of new HIV-1 strainsIsolation of new HIV-1 strains

Viruses isolated from early seroconverters or patients with acute HIV-1 infection;

Most strains have the S/L phenotype; 70% strains fail to infect PBMC,

7% strains are dual tropic and phenotypically intermediate (between S/L- and R/H-forms).

Phenotypic properties of transmitted founder Phenotypic properties of transmitted founder HIV-1 (new mosaic viruses A1 HIV-1 (new mosaic viruses A1 CRF63_02AG) CRF63_02AG)

More infectious; More Env per particle; Increased interaction with DC; More resistant to interferon alpha.

20. We [the G8 leaders)] remain committed to our Sea Island Summit initiative on creation of a Global HIV Vaccine Enterprise, and reaffirm our determination to bring it to fruition. We are convinced that there is a need to enhance the scientific and technical capacities in this area at the global, regional and national levels. In this regard, we welcome the Russian proposal to establish a regional coordination mechanism to promote HIV vaccine development in the countries of Eastern Europe and Central Asia, and call for this initiative to be carefully coordinated with the Global HIV Vaccine Enterprise. We also welcome  coordination of activities and the cooperation between the Global HIV Vaccine Enterprise and other global initiatives and North/South partnerships active in this field, such as the European and Developing countries Clinical Trials Partnership (EDCTP) on clinical trials in Africa.

G8 declaration on the fight G8 declaration on the fight

against infectious diseases against infectious diseases St. PetersburgSt. Petersburg, , July July 1616, , 20062006

Acknowledgments:

Institute of Virology,RussiaG. Kornilaeva,F. Moskaleichik,A. Tatarintsev,A. Turgiev

Institute of Immunology,RussiaR. Khaitov, M. Khaitov,I. Sidorovich

Instituto de Salud Carlos III,SpainM. Thomson

National Cancer Institute,U.S.A.B. O’Keefe