These are present on the native protein but are only partially expressed on the unfolded denatured protein [ 25 ]. The viral envelope is composed of a lipid bi-layer and, in mature virus particles, the envelope proteins SU and TM. It covers the symmetrical outer capsid membrane which is formed by the matrix protein MA, p The conical capsid is assembled from the inner capsid protein p24 CA [ 26 ].
Depending on the section plane, the capsid appears as a cone, a ring or an ellipse in electron micrographs fig.
The tapered pole of the capsid is attached to the outer capsid membrane. Also present in virus particles are oligopeptides that are generated after release from the cell during the maturation of virions by proteolytic processing of the precursor proteins p55, p In electron microscopic investigations, loss of surface projections SU trimers as a result of shear forces - also known as shedding - can be observed after release [ 27 ]. Particles free of gp are no longer infective [ 28 ].
Tat accelerates the availability of viral RNA for virus production approximately fold. Furthermore, Tat is able to transactivate additional HIV genomes present in the cell. This enables the production of regulatory proteins early during replication, followed by translation of structural proteins in the late stage of the replication cycle. Nef has a negative effect on the presentation of CD4 molecules on the cell surface.
Therefore, the membrane of the infected cell becomes deficient in CD4 and cannot be superinfected by additional HIV see below. The loss of CD4 decelerates the cellular immune reaction against the infected cell. Moreover, Nef enhances pathogenicity in vivo and is required for the progression of the infection [ 5 ].
Additional regulatory proteins are Vif, Vpr and Vpu which influence the rate of the production of virus particles [ 8 , 30 , 31 ].
Molecular biological methods are not capable of distinguishing HIV-2 isolates of groups A-H from isolates of mangabeys [ 32 ]. So far, none of these viruses have been transmitted to humans to induce infection chains. Due to distinct differences between HIV-1 and HIV-2 in the antigenicity of the viral proteins and in the genome structure, HIVspecific diagnostic tools are required. NAT tests for quantification of HIV-2 nucleic acids have been commercially available since [ 38 ].
The initial steps of infection of a cell are characterised by complex protein-protein interactions. The surface glycoprotein gp of the mature HIV particle binds to the CD4 receptor on the host cell. After attachment to the CD4 molecule via the C4-domain of gp, a conformational change in CD4 and gp occurs, opening up an additional site for gp to enable binding to the co-receptor, i.
Binding of gp to CD4 and to the co-receptor triggers an additional conformational change in gp and subsequently in gp41 [ 1 , 41 ]. The N-terminus of gp41 is presented on the viral membrane, forms a channel and, due to its high hydrophobicity, inserts into the plasma membrane of the target cell.
Fusion of cell membrane and viral envelope is then completed. Fusion of the viral and cellular membranes leads to translocation of the viral capsid into the cytoplasm. The capsid is taken up by an endosome, and a change in the pH value in the phagosome induces the release of the capsid contents into the cytoplasm [ 42 ]. Activation of reverse transcriptase RT takes place in the cytoplasm.
This proviral DNA is transported via nucleopores into the cell nucleus in the form of a complex consisting of the integrase IN and linear or circular proviral DNA. The integrase then inserts at random the proviral genome into the human host cell genome. Integration of the proviral DNA finalises the HIV infection of the cell and the establishment of a persistent infection.
The proviral genome can be replicated together with and as part of the host cell genome during cell division latent infection which seems to be rare. The synthesis of full-length viral mRNA is regulated among others by Tat and maximally accelerated by Tat p14 [ 44 ]. The attachment of HIV to a CD4-positive cell requires around 30 min up to 2 h, the transcription of the viral RNA genome into the proviral DNA is completed after approximately 6 h, and the integration into the host genome takes an additional 6 h.
After integration, the first virus particles are detectable after approximately 12 h; i. Because the viral RT has no proofreading activity, statistically one incorrect nucleotide per transcription round is incorporated into the proviral DNA.
If HIV replication is unrestricted a daily turnover of 10 8 9 viral particles is expected, i. Assuming a mutation rate of 1 in 10 4 nucleotides per genome during one replication cycle, a broad spectrum of various quasispecies can therefore develop in a patient in the course of time.
Since epitopes for neutralising antibodies are also affected by mutation, these quasispecies are able to continually evade the immune system, infect new cells and therefore maintain HIV production [ 25 , 29 ].
Not all nucleotide changes result in the exchange of an amino acid. However, mutations in essential regions of the structural proteins or influencing active centres of enzymes give rise to replication-incompetent HIV mutants. Infected T lymphocytes are eliminated with a half-life of days from the blood of an HIV-infected person by cytotoxic HIV components, lysis of virus-producing cells or by cytotoxic T lymphocytes as part of the immune response [ 48 , 49 ].
Since HIV-infected T helper cells are also lysed and the production of such cells is inhibited simultaneously, a gradual decline of T helper cells is observed.
HIV-specific proteins like Nef and Tat are responsible for insufficient maturation and replacement of T helper cells [ 29 ]. Therefore, part of the newly produced T helper lymphocytes do not develop normal functions [ 47 ]. After a long-lasting HIV infection the continuous loss of T helper lymphocytes results in immunodeficiency. HIV integrated into the host genome of long-lived cells like macrophages, astrocytes or memory T cells can persist in the latent stage for several years half-life of certain target cells is 7 years.
Activation of such cells results in the production of infectious HIV particles. The lipid envelope primarily characterises the stability of HIV. HIV is stable for several hours at a pH between 3 and 10 [ 50 , 51 ]. HIV is sensitive against disinfectants. HIV is stable over several hours against the influence of physical conditions like ultraviolet light, gamma irradiation or ultrasonic waves [ 53 , 54 ].
In contrast to other viruses, treatment of platelet concentrates with UVC light reduced HIV titres only slightly [ 55 ]. Therefore in a blood donation only a titre reduction of 1. Taking into consideration that one human infectious dose HID corresponds to approximately , HIV particles, a small amount of transfused blood is sufficient to transmit an HIV infection, although exceptions were observed occasionally [ 58 ].
The infectivity of HIV particles in lymphocytes is variable. It has to be assumed that processed HIV in lymphocytes is inactivated more rapidly than in plasma. In dendritic cells HIV can remain infectious for several weeks [ 41 ]. In lyophilised plasma or factor concentrates, HIV is stable at room temperature for years in the presence of high protein concentrations. HIV is able to enter the body via intact mucous membranes, eczematous or injured skin or mucosa and by parenteral inoculation.
When transmitted by sexual contact, HIV attaches first to dendritic cells e. HIV is taken up by macrophages and replicated [ 60 ] as shown for M cells in the mucosa [ 61 ]. HIV exposure to blood cells can result in the direct infection of T helper cells and the transmission of R5 and X4 viruses using CXC4 receptor as a co-receptor [ 62 ]. As mentioned above, 1 HID is equivalent to approximately , HIV particles, with a higher dose required for infection via mucous membranes compared to infection via the bloodstream, e.
The majority of new HIV infections are still transmitted sexually. Another epidemiologically relevant route is parenteral administration of drugs and also snorting of drugs with epistaxis.
One to two days after infection HIV can be detected in regional lymphatic tissue [ 63 ] and within days in regional lymph nodes. After days post infection HIV can be detected in the whole body, including the nervous system. Differences in the rate of dissemination of HIV in the body have been observed, depending on the primary target cells infected, e. Within an infected organism, distinct compartments can be distinguished by means of virus concentration; however, no correlation between virus concentrations in the different compartments is obvious.
HIV-relevant compartments are blood and the cerebrospinal and genital systems ejaculate or vaginal secretion [ 65 , 66 ]. Transmission of HIV via blood or transplanted organs, including bone, is possible from about days after infection of the donor. HIV can be transmitted via breast milk [ 68 ]. These symptoms are non-specific and are also found in other viral infections such as EBV- and CMV-induced mononucleosis or influenza.
Acute neuropathy is common in the acute phase. The symptoms persist for weeks. This initial symptomatic phase is usually followed by an asymptomatic phase or one with occasional symptoms which can last for many years. Therefore blood donations are highly infectious during this phase. However, in this phase blood and cervicovaginal secretions or seminal fluids of infected persons are still infectious.
Diagram of the temporal course of an untreated HIV infection. The time scale is initially weeks acute phase , then months and finally years stages 2 and 3. The key feature of viraemia is the undulation after the initial uninhibited HIV replication.
The CD4 cell count decreases over time despite repeated recovery phases. HIV antibodies remain measurable for life, and the decrease of antibody response in stages 2 and 3 results from loss of core antibodies anti p55, p24 and p The overall interval from infection with the virus to the onset of AIDS may vary without therapy from 2 to 25 years or longer. Depending on the immune response and the test systems used, the commercially available antibody screening tests are able to detect HIV-specific antibodies in the plasma approximately as of the third week post infection, typically after weeks and in the case of a delayed immune response after 8 weeks see 1.
At the beginning of the immune response low titres of IgM and IgG antibodies are detectable that are mainly directed against p24 and the surface glycoproteins gp and gp Subsequently, high-avidity IgG antibodies against all HIV proteins are developed, typically within weeks. A specific T-cell response is induced against a variety of epitopes of HIV proteins [ 76 ]. Like in other virus infections, the early immune response leads to an IgM antibody response that can persist for months [ 5 ].
A high portion of the neutralising antibodies is directed against the V3 loop of gp Such antibodies are strain-specific and are not able to sufficiently eliminate all HIV quasispecies which are continuously produced in the infected individual [ 25 , 77 , 78 ].
Under the pressure of the immune response, viruses with a variable V3 loop are selected. The V3 loop is the region of the gp protein hypervariable region in which high numbers of mutations are observed, resulting in amino acid exchanges.
No serologic subtype differentiation is possible, but this can be achieved by determining the subtype-specific amino acid sequences of the C2V5 region of gp [ 8 ]. In the course of the HIV infection and depending on the number of CD4 cells, at first unspecific symptoms can be observed.
These can include short episodes of fever, diarrhoea, malaise, fatigue and loss of weight symptoms of the so-called AIDS-related complex, ARC. Characteristic features of an HIV infection are periods of good health followed by periods of illness which become more frequent and longer-lasting in the course of the infection [ 79 , 80 ].
Time to occurrence of apparent symptoms of immunodeficiency varies from 2 to 25 years or more fig. As mentioned above, impairment of neurologic and cerebral functions can emerge at any stage of infection. Frequently occurring opportunistic pathogens are Toxoplasma gondii , Cryptosporidium parvum , Pneumocystis jirovecii , Mycobacterium tuberculosis and atypical mycobacteria, Salmonella spec.
Patients with HIV infections lasting for years develop marasmus which is a characteristic outward manifestation of untreated patients [ 5 ]. Concurrent infection with hepatitis C virus HCV results in faster progression of both virus-induced diseases [ 81 , 82 , 83 ]. Some HIV-infected patients develop characteristic atrophic skin alterations or seborrhoeic eczema that are visible manifestations of the HIV infection.
Likewise at an early stage of the infection changes of the oral mucosa are detectable, with gingival retraction and deep periodontal lesions as well as hairy leucoplakia on the lateral rim of the tongue or on the buccal mucosa [ 84 ]. Subdivision includes the CD4 cell count. According to present knowledge, the spread of HIV started at the beginning of the 20th century [ 4 , 86 ].
HIV-2 was transmitted zoonotically from sooty mangabey Cercocebus atys to human in West Africa around [ 87 ]. Molecular genetic analyses suggest that HIV-1 was exported to Haiti probably in and arrived in North America approximately 2 years later [ 4 , 88 ]. Since the mids the different HIV-1 M subtypes have been spreading, leading to a global pandemic. Globally, an estimated 35 million people were living with HIV in [ 89 ]. Since the number of new infections has been decreasing continuously, and for a number of 1.
About three quarters of HIV-infected persons live in Sub-Saharan Africa, and also about two-thirds of the reported new infections originate from this region. The data on the HIV epidemic in Germany are mainly based on the implemented obligatory reporting system.
Reporting must be performed by the diagnosing laboratory also the diagnosing blood establishment. The physician submitting the specimen receives a copy of the reporting form. The physician is required to supply demographic, anamnestic and clinical data which are not available to the laboratory.
The completed reporting form is sent directly to the Robert Koch Institute. The available surveillance instruments provide data on specific aspects of the HIV epidemic. Therefore, the Robert Koch Institute regularly generates estimations of the course of the HIV epidemic, taking into account the available data and information from the various sources. Determination of the number of new HIV infections per time unit HIV incidence by means of official reporting data is not possible because the reports of HIV diagnoses do not allow direct conclusions about the date of infection.
HIV incidence and HIV prevalence cannot be measured directly but only estimated by means of model projections. At first, the estimated number of new HIV infections in all age groups has decreased significantly in the course of time up to the end of the s, with peak values in the mids.
From to around a significant increase of HIV infections was observed, with a plateau since Approximately women In addition, HIV infections were observed in about 9. The trends in the three main groups affected in Germany proceeded differently: the first peak of infections occurred simultaneously in the groups of MSM and IVD in the mids. In the following years up to the beginning of the s, the number of new HIV infections decreased significantly in both groups.
This trend continued in the group of IVD up to with a largely constant low level of new infections since Also in the group of MSM significantly fewer infections occurred during the s. However, in the period between and a significant increase in HIV infections in MSM was observed and reached a considerably higher plateau in The number of those infected via heterosexual contacts hetero-domestic in Germany has been rising significantly slower in the course of the epidemic than in the MSM and IVD groups.
Since the number of new infections in heterosexually infected persons has remained on a constant level. Autonomous heterosexual infection chains have a minor impact on the spread of the HIV epidemic in Germany.
Considering the number of reported new infections, large regional differences can be observed. Especially in densely populated urban areas among others Rhine-Ruhr, Rhine-Main and major cities, the incidence of new diagnoses is much higher than in the remaining regions. In , the ratio of men to women in the group of new infections was 3.
Since the percentage of newly diagnosed cases has been rather stable. In Eastern Europe i. Newly diagnosed HIV infections and modes of transmission in different European countries in www. The molecular epidemiologic data show that HIV-1 group M subtypes have different regional prevalence patterns. The prevalence of HIV-1 subtypes and HIV-2 in European countries reflects the historic connection of these countries to the corresponding endemic regions in Africa [ 12 , 17 , 93 ].
Africa is the continent that is affected most by HIV infections. The estimated HIV prevalence in Africa varies widely and lies between 0. Heterosexual contacts are the main route of infection in Africa, and sex work and sexual violence contribute significantly to the spread of the disease.
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