Table 1.

Studies on AAV infection and HPV-related cervical cancer in humans

References	Year	Country	Study population	Samples	Results	Conclusions
[57]	1976	USA	Cases = 120 Control = 128	Serum	Presence of IgG antibodies to AAV type 2–3 complex in genital cancer cases was 14% and in healthy women was 85% (P < 0.001).	The percentage of sera with antibodies to AAV was significantly higher in the normal group than in the cancer patients. The role of AAV in possible abrogation of oncogenesis mediated through adenoviruses or herpesviruses is worthy of further investigation.
[58]	1984	Germany	Cases = 83 Control = 50	Serum	The control group exhibited approximately three-fold higher IgG antibodies titers against AAV type 5 than cervical cancer patients.	The data could suggest that AAV infection provides some protection against subsequent cervical cancer development.
[62]	1999	Jamaica USA	Jamaican patients: Cases = 197 (CIN-1 = 105; CIN-3/CA = 92) Control = 94 U.S. patients: Cases = 74 Control = 77	Cervical smear (Jamaica); serum (USA)	None of the 291 cervical specimens from Jamaican subjects tested positive for AAV DNA. No relationship between IgG antibodies to AAV type 2 and presence or grade of neoplasia in either the Jamaican or U.S. cervical cancer cases.	The data provide no evidence that AAV infection plays a role in cervical tumorigenesis or that AAV commonly infects cervical epithelial cells.
[63]	2000	United Kingdom	Cases = 211 (CIN-1 = 83; CIN-3 = 128) Control = 433	Cervical smear	6/433 (1.4%) control cervical smears and 4/211 (1.9%) of CIN (CIN-1 = 2; CIN-3 = 2) contained AAV type 2 DNA. No correlation between AAV and any clinical feature was observed.	AAV DNA is not frequently present in either normal control cervical samples or cervical intraepithelial neoplasia. This does not support the hypothesis that AAV may be protective against cervical cancer.
[59]	2001	USA	Cases = 217 (HSIL = 55; LSIL = 162) Control = 96	Cervical smear	AAV positivity was associated with a significantly reduced risk of HSIL (age and HPV-adjusted odds ratio (aOR) = 0.32) yet not with LSIL (aOR = 0.78); 53.8% of HSIL, 66.9% of LSIL, and 70.7% of controls were AAV+.	AAV may play a protective or inhibitory role in late stage cervical carcinogenesis.
[64]	2003	South Korea	Cases = 92 (CIN-1 = 20; CIN-2 = 24; CIN-3 = 25; invasive = 23) Control (perilesional normal tissues) = 92	Cervical tissue	AAV type 2 was detected in 55% of CIN-1, 84.5% of CIN-2, 52% of CIN-3, and 52.2% of invasive cancer cases. In perilesional normal tissues, AAV was detected in 57.6%, displaying 25% of CIN-1, 83.3% of CIN-2, 52% of CIN-3, and 65.2% of invasive cancer.	The differences in AAV prevalence are not significant between CIN and normal tissues, suggesting no significant correlation between AAV and cervical cancer.
[65]	2004	Croatia	165 nonpregnant and 53 pregnant women with cervical cancer.	Cervical smear	AAV type 2 DNA was found in 6% of the women. AAV infection was more frequently associated with pregnancy (17 versus 2.4%).	There is no evidence that AAV infection has any impact on cervical cancer development. These data point out that HPV could indeed be an AAV helper virus and that AAV as such can be considered sexually transmissible.
[66]	2006	Sweden	Cases = 104 Matched control = 104	Cervical smear; cervical tissue	At baseline, 2% of case-women and 3% of control-women were positive for AAV type 2 DNA. At the time of cancer diagnosis, 12% of case-women and 3% of matched control-women were positive for AAV DNA.	AAV DNA was present in a low proportion of cervical cancers. No evidence that the presence of AAV in cervical smears of healthy women would be associated with reduced risk of cervical cancer.
[60]	2008	Greece	Cases = 93 (CIN-1 = 31; CIN-2/3 = 45; invasive = 17) Control = 280	Cervical smear	AAV infection was confirmed in 16.8% women, and AAV detection was not statistically different between HPV (–) and HPV (+) in the controls. AAV was significantly lower in the HPV (+) relative to the HPV (–) cancer patients.	HPV-infected individuals are less likely to develop cervical neoplasia if AAV is present. AAV probably demonstrates a protective role against the pathogenic consequences of HPV infection.
[61]	2012	Brazil	284 women (HIV positive = 112; HIV negative = 172	Cervical smear	AAV type 2 prevalence was 19.7%, with 18.7% and 20.3% in HIV-positive and -negative women, respectively. AAV was detected with higher frequency in HPV-infected women (P < 0.05). The AAV-HPV co-infected women showed a lower rate of atypical squamous cells of undetermined significance or cervical intraepithelial neoplasia development compared with those infected only with HPV.	This is the first report examining AAV in cervical samples of HIV-infected women and indicates that HIV infection does not appear to influence AAV prevalence or AAV-HPV co-infection.
[67]	2017	Iran	Cases = 61 Control = 50	Cervical tissue	AAV type 2 DNA was detected in 7 cases (14%) of healthy controls and 9 specimens (14.8%) of case group.	A low proportion of cervical biopsies from Iranian women contained AAV genome. The correlation between HPV and cervical cancer showed no significant difference in presence or absence of AAV genome in cervix.

CIN-1, low-grade cervical intraepithelial neoplasia; CIN-3/CA, CIN-3/carcinoma in situ or invasive cancer; HSIL, high-grade cervical squamous intraepithelial lesions; LSIL, low-grade cervical squamous intraepithelial lesions