Perinatal HIV-1 infection : aspects on clinical presentation, viral dynamics and epidemiology

During the last 20 years HIV-1 infection has changed from being an unknown disease to being a widespread pandemic, in some areas affecting a large proportion of the human population. Mother-to-child transmission (MTCT) is the predominant route of transmission in children, who thus become infected during a period when their immune system is immature and developing. This thesis is based on a prospective follow-up of a population-based cohort of children to HIV-1-infected women in Sweden since the start of the HIV-1 epidemic.

We followed a total of 419 mother-child pairs between 1982 and 2003, 355 of them prospectively. The MTCT rate decreased during the period from 24.7% 1984-93 to 5.7% 1994-98 and 0.7% 1999-2003. The proportion of children born to women who received antiretroviral treatment or prophylaxis increased from 2.3% to 91.5%, and the elective caesarean section rate from 8.0% to 80.1%. Seventy-two children, 31 of whom were born in Sweden, were vertically infected. Eleven infected children died. Ten out of 51 children living in Sweden in 2003 had had an AIDS diagnosis and 29 were on antiretroviral treatment. Eleven lived with a non-parental caregiver.

In 24 prospectively followed HIV-1-infected children born during 1985-98, the disease progressed faster to severe immunodeficiency, AIDS or death in children with early symptoms related to HIV-1 than in those without early symptoms. Detectable virus during the first four days of life was not shown to affect disease progression. Two children developed symptoms suggestive of primary HIV-1 infection.

HIV-1 RNA load was determined in 32 infected children. The median HIV-1 RNA level was highest at 1.5-3 months of age, decreased between 1 and 8 years and then increased slightly. This pattern was not seen in all individuals. Both symptomatic and asymptomatic children displayed a varying pattern of viral load.

Stored samples from 24 infected children were analysed for genetic subtype and coreceptor use of the virus. The virus belonged to subtypes A, B, C, D, G and CRF01_AE. All isolates from the first year of life used chemokine receptor CCR5 as coreceptor. In virus from four patients, the coreceptor use changed from CCR5 to CXCR4. The change was associated with a decreased CD4+ cell count and disease progression, but appeared after immunological deterioration.

Infectious viral loads by limiting dilution culture and days-to-culture positivity (infectious index) and HIV-1 RNA were determined in 16 children. Limiting dilution correlated to the infectious index. The median HIV-1 RNA and infectious indices of plasma and PBMC rose rapidly to 6-8 weeks of age to a plateau level. The median index in plasma declined to zero by 2 years of age in contrast to that in PBMC and to HIV-1 RNA. A high-peak plasma index correlated with clinical progression. Children who progressed to AIDS had higher median plasma indices than those who did not. In children displaying a coreceptor change in plasma, there was a simultaneous reappearance of infectious virus, which was not related to changes in RNA.

In summary, the virological studies contribute to a better knowledge of the natural course and interaction between virus and host in perinatally HIV-1 infected children. The epidemiological study shows that good results can be achieved if prophylactic measures against MTCT of HIV-1 are used consistently, which highlights the importance of antenatal screening programmes.

List of scientific papers

I. Naver L, Ehrnst A, Belfrage E, Blomberg J, Christensson B, Forsgren M, Lidin-Janson G, Lindgren S, Ljung R, Sonnerborg A, Bohlin AB (2001). Broad spectrum of time of detection, primary symptoms and disease progression in infants with HIV-1 infection. Eur J Clin Microbiol Infect Dis. 20(3): 159-66.
https://pubmed.ncbi.nlm.nih.gov/11347664

II. Naver L, Ehrnst A, Belfrage E, Sonnerborg A, Lidin-Janson G, Christensson B, Ljung R, Bohlin AB (1999). Long-term pattern of HIV-1 RNA load in perinatally infected children. Scand J Infect Dis. 31(4): 337-43.
https://pubmed.ncbi.nlm.nih.gov/10528869

III. Casper C, Naver L, Clevestig P, Belfrage E, Leitner T, Albert J, Lindgren S, Ottenblad C, Bohlin AB, Fenyo EM, Ehrnst A (2002). Coreceptor change appears after immune deficiency is established in children infected with different HIV-1 subtypes. AIDS Res Hum Retroviruses. 18(5): 343-52.
https://pubmed.ncbi.nlm.nih.gov/11897036

IV. Naver L, Bohlin AB, Belfrage E, Casper C, Clevestig P, Ehrnst A (2004). HIV-1 infectious viral load relation to RNA and pathogenesis in perinatally HIV-1-infected children. [Submitted]

V. Naver L, Lindgren S, Belfrage E, Gyllensten K, Lidman K, Gisslen M, Arneborn M, Bohlin AB (2004). Children born to HIV-1-infected women in Sweden in 1982-2003: Long-term follow-up and trends in epidemiology and vertical transmission. [Manuscript]