The influence of coinfections and host genetic factor on the susceptibility to HIV infection among people who inject drugs
Date
2019-05-09
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Abstract
Parenteraalne ülekanne on kõige efektiivsem HIV-i ülekandetee. Sellest lähtuvalt peetakse süstivaid narkomaane (SN) üheks kõige haavatavamaks grupiks. SN-de seas läbi viidud uuringud on paljastanud mitmeid isikuid, kes riskikäitumisele vaatamata ei nakatu HIV-ga. Lisaks geneetilistele polümorfismidele võivad HIV-i nakatumist mõjutada ka kaasuvad infektsioonid, mis suurendavad immuunsüsteemi koormust ja võivad seeläbi mõjutada organismi vastuvõtlikkust. Mõned viirused, nt inimese T-lümfotroopne viirus (HTLV) ja inimese pegiviirus (HPgV), avaldavad HIV-le inimese seisukohast kasulikku mõju.
Käesoleva uurimustöö eesmärgiks oli HIV-ga kaasuvate infektsioonide (HTLV-1/2, HPgV) ja interferoon-lambda-4 (IFNλ4) geenis paikneva polümorfismi kirjeldamine ning nende mõju hindamine HIV-i nakatumisele. Selleks kaasati 345 SN-i, kontrollgruppidena kasutati terveid vabatahtlikke ja veredoonoreid.
HTLV-1/2 määramisel tuvastasime ühe HTLV-2 positiivse SN-i, teised olid HTLV-1/2 negatiivsed. Kõik terved vabatahtlikud olid HTLV-1/2 negatiivsed. HPgV vireemiat esines kolmandikul SN-del, kuid antikehade esinemine oli oluliselt harvem. Tervete vabatahtlike seas oli HPgV vireemia viis korda madalama sagedusega, kuid antikehade sagedus oli sarnane SN-dega (vastavalt 1,7% ja 2,3%). Kõrge HPgV vireemia SN-de seas võib osaliselt tuleneda nende riskikäitumisest, aga ka HIV-i ja teiste infektsioonide poolt tekitatud immuunsüsteemi kahjustustest, mille tulemusena ei suudeta HPgV-st vabaneda ning infektsioon muutub krooniliseks. Madal HPgV antikehade tase võib tuleneda HPgV iseärasustest – vireemiale ei järgne alati antikehade teke ja tekkinud antikehad võivad kaduda. IFNλ4 rs12979860 puhul ei leidnud me seoseid rs12979860 genotüüpide ja HCV-ga nakatumise vahel. Samas, rs12979860 TT genotüübi kandjatel olid ligi kaks korda suuremad šansid olla HIV positiivne. Interaktsioonanalüüs näitas, et TT genotüübi avaldatud mõju vähenes süstimisaja kasvades.
Kokkuvõttes on HTLV-1/2 väga harva esinev, mistõttu pole rutiinne testimine HTLV-1/2 suhtes tõenäoliselt kulutõhus. Samas on HPgV SN-de seas sage ning võib mõjutada HIV-i kulgu siin piirkonnas. IFNλ4 rs12979860 mõjutab küll HIV-i nakatumist, kuid jätkuv riskikäitumine vähendab antud polümorfismi mõju suurust.
Parenteral modes are the most efficient routes of HIV transmission and thus, people who inject drugs (PWID) are considered to be one of the most vulnerable groups. However, PWID populations often reveal a number of individuals who despite being highly exposed do not get infected. In addition to genetic polymorphisms, coinfections may also play a role in HIV acquisition. Although most coinfections have adverse effects on HIV some (e.g. Human T-lymphotropic virus [HTLV] and Human Pegivirus [HPgV]) have beneficial. The aim of this thesis was to describe the prevalence of HIV coinfections (HTLV-1/2, HPgV) and a polymorphism in the interferon-lambda-4 gene (IFNλ4) and to evaluate their association with HIV acquisition. The study was conducted among 345 PWID. Healthy volunteers and blood donors were used as control groups. We found one of the PWID to be HTLV-2 positive and the rest were HTLV-1/2 negative. As expected, all healthy volunteers were negative for HTLV-1/2. HPgV viremia was present in third of PWID but the prevalence of HPgV seropositivity was significantly lower. The rate of HPgV viremia was five times lower among healthy volunteers but the rate of seropositivity was similar to PWID (1,7% and 2,3%, respectively). High rate of HPgV viremia among PWID might at least partially be due to their risk behaviour but it may also suggest that they are unable to clear HPgV viremia due to the immunocompromising effect of HIV and other infections. The low HPgV seropositivity detected in our study could be due to characteristics inherent to HPgV infection – the clearance of viremia is not always followed by the production of antibodies and produced antibodies might disappear over time. The IFNλ4 rs12979860 study revealed no associations between rs12979860 genotypes and HCV acquisition. However, we found the TT genotype to increase the susceptibility to HIV. According to the interaction analysis the scale of the influence of TT genotype decreased with increasing duration of intravenous drug use. In conclusion, HLTV-1/2 is rare in Estonia suggesting that there is no need for routine testing for these viruses. HPgV is common among PWID and could affect HIV acquisition and disease progression in this area. IFNλ4 rs12979860 TT genotype increases susceptibility to HIV but continuing risk behaviour diminishes the impact of this polymorphism.
Parenteral modes are the most efficient routes of HIV transmission and thus, people who inject drugs (PWID) are considered to be one of the most vulnerable groups. However, PWID populations often reveal a number of individuals who despite being highly exposed do not get infected. In addition to genetic polymorphisms, coinfections may also play a role in HIV acquisition. Although most coinfections have adverse effects on HIV some (e.g. Human T-lymphotropic virus [HTLV] and Human Pegivirus [HPgV]) have beneficial. The aim of this thesis was to describe the prevalence of HIV coinfections (HTLV-1/2, HPgV) and a polymorphism in the interferon-lambda-4 gene (IFNλ4) and to evaluate their association with HIV acquisition. The study was conducted among 345 PWID. Healthy volunteers and blood donors were used as control groups. We found one of the PWID to be HTLV-2 positive and the rest were HTLV-1/2 negative. As expected, all healthy volunteers were negative for HTLV-1/2. HPgV viremia was present in third of PWID but the prevalence of HPgV seropositivity was significantly lower. The rate of HPgV viremia was five times lower among healthy volunteers but the rate of seropositivity was similar to PWID (1,7% and 2,3%, respectively). High rate of HPgV viremia among PWID might at least partially be due to their risk behaviour but it may also suggest that they are unable to clear HPgV viremia due to the immunocompromising effect of HIV and other infections. The low HPgV seropositivity detected in our study could be due to characteristics inherent to HPgV infection – the clearance of viremia is not always followed by the production of antibodies and produced antibodies might disappear over time. The IFNλ4 rs12979860 study revealed no associations between rs12979860 genotypes and HCV acquisition. However, we found the TT genotype to increase the susceptibility to HIV. According to the interaction analysis the scale of the influence of TT genotype decreased with increasing duration of intravenous drug use. In conclusion, HLTV-1/2 is rare in Estonia suggesting that there is no need for routine testing for these viruses. HPgV is common among PWID and could affect HIV acquisition and disease progression in this area. IFNλ4 rs12979860 TT genotype increases susceptibility to HIV but continuing risk behaviour diminishes the impact of this polymorphism.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone
Keywords
narkomaanid, HIV-nakkused, kaasnevad haigused, HIV-positiivsed, geneetiline polümorfism